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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open
access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also
more traditional review articles (“deep insights”) on the above subjects and on surrounding topics.
It also present case reports in hematology and educational items in the various related topics for students in Medicine
and in Sciences.
Editorial correspondance
Jean-Loup Huret
Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
[email protected] or [email protected]
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a
non profit organisation.
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy
Institute – Villejuif – France).
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open
access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also
more traditional review articles (“deep insights”) on the above subjects and on surrounding topics.
It also present case reports in hematology and educational items in the various related topics for students in Medicine
and in Sciences.
Editorial correspondance
Jean-Loup Huret
Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
[email protected] or [email protected]
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a
non profit organisation.
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy
Institute – Villejuif – France).
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the
Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research
(CNRS) on its electronic publishing platform I-Revues.
Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Editor
Jean-Loup Huret
(Poitiers, France)
Volume 6, Number 4, October - December 2002
Table of contents
Gene Section
FANCA (Fanconi anaemia complementation group A)
Jean-Loup Huret
270
FANCC (Fanconi anaemia complementation group C)
Jean-Loup Huret
273
FANCD2 (Fanconi anemia, complementation group D2)
Jean-Loup Huret
275
FANCE (Fanconi anemia, complementation group E)
Jean-Loup Huret
277
FANCF (Fanconi anemia, complementation group F)
Jean-Loup Huret
279
FANCG (Fanconi anemia, complementation group G)
Jean-Loup Huret
281
PLAG1 (Pleomorphic adenoma gene 1)
David Gisselsson
283
Leukaemia Section
Angioimmunoblastic T-cell lymphoma
Antonio Cuneo, Gianluigi Castoldi
286
Lymphoepithelioid lymphoma
Antonio Cuneo, Gianluigi Castoldi
288
t(2;14)(p13;q32)
Jean-Loup Huret
289
t(5;14)(q35;q32)
Roland Berger
290
Acute Erythroid leukaemias
Sally Killick, Estella Matutes
292
t(1;13)(q32;q14)
Jean-Loup Huret
294
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
t(11;14)(q13;q32)
in multiple myeloma
Atlas
of Genetics
and Cytogenetics
in Oncology and Haematology
Huret JL, Laï JL
OPEN ACCESS JOURNAL AT INIST-CNRS
t(1;7)(q21;q22)
Jean-Loup Huret
296
t(3;14)(q21;q32)
Jean-Loup Huret
297
t(4;11)(q21;p15)
Franck Viguié
298
t(6;8)(q11;q11)
Jean-Loup Huret
300
Solid Tumour Section
Head and neck squamous cell carcinoma
Hélène Blons
301
Cancer Prone Disease Section
Congenital neutropenia
Jay L Hess
304
Simpson-Golabi-Behmel syndrome
Daniel Sinnett
306
Fanconi anaemia
Jean-Loup Huret
308
Tuberous sclerosis (TSC)
Julie Steffann, Arnold Munnich, Jean-Paul Bonnefont
311
Deep Insight Section
Ataxia-Telangiectasia and variants
Nancy Uhrhammer, Jacques-Olivier Bay, Susan Perlman, Richard A Gatti
313
Educational Items Section
Genetic Linkage Analysis
Françoise Clerget-Darpoux
323
Consanguinity
Robert Kalmes, Jean-Loup Huret
334
Genealogy and Coefficient of Consanguinity, Exercices
Robert Kalmes
339
Genetic Constitution of Consanguine Populations
Robert Kalmes, Jean-Loup Huret
341
Prenatal Diagnosis
Louis Dallaire
342
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
FANCA (Fanconi anaemia complementation group
A)
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Genes/FA1ID102.html
DOI: 10.4267/2042/37891
This article is an update of:
Joenje H. FANCA (Fanconi anaemia A). Atlas Genet Cytogenet Oncol Haematol.2002;6(2):82-84.
Huret JL. FA1 (Fanconi anaemia 1). Atlas Genet Cytogenet Oncol Haematol.1998;2(3):81-82.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Function
Identity
Part of the FA complex with FANCC, FANCE,
FANCF, and FANCG; this complex is only found in
the nucleus.
FANCA and FANCG form a complex in the
cytoplasm, through a N-term FANCA (involving the
nuclear localization signal) - FANCG interaction;
FANCC join the complex; phosphorylation of FANCA
would induce its translocation into the nucleus.This FA
complex translocates into the nucleus, where FANCE
and FANCF are present; FANCE and FANCF join the
complex. The FA complex subsequently interacts with
FANCD2 by monoubiquitination of FANCD2 during S
phase or following DNA damage. Activated
(ubiquinated) FANCD2, downstream in the FA
pathway, will then interact with other proteins involved
in DNA repair, possibly BRCA1; after DNA repair,
FANCD2 return to the non-ubiquinated form.
Other names: FACA; FAA; FA1
HGNC (Hugo): FANCA
Location: 16q24.3
DNA/RNA
Description
43 exons spanning 80 kb; 4365 bp open reading frame.
Transcription
5.5 kb mRNA
Protein
Description
1455 amino acids; 163 kDa; 2 nuclear localisation
signals (NLS) consensus sequences in N-terminus and
a leucine zipper in 1069-1090, none proven to
functional
as
such;
FANCA
is
normally
phosphorylated.
Homology
No known homology or functional motifs.
Mutations
Expression
Germinal
Wide: brain, placenta, testis, tonsils (mRNA); in mice:
protein expression predominant in lymphoid organs,
testis, ovary.
Various nucleotide substitutions, deletions, or
insertions have been described. Over 90% of the
mutations are private, with about 30% being relatively
large deletions. Founder mutations have been described
in South Africa.
Localisation
Both cytoplasmic and nuclear.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
270
FANCA (Fanconi anaemia complementation group A)
Huret JL
Implicated in
an arginine-rich domain.
26;274(48):34212-8
Fanconi anaemia (FA)
Kupfer G, Naf D, Garcia-Higuera I, Wasik J, Cheng A,
Yamashita T, Tipping A, Morgan N, Mathew CG, D'Andrea AD.
A patient-derived mutant form of the Fanconi anemia protein,
FANCA, is defective in nuclear accumulation. Exp Hematol.
1999 Apr;27(4):587-93
FANCA is implicated in the FA complementation
group A; it represents about 70% of FA cases.
Disease
Fanconi anaemia is a chromosome instability
syndrome/cancer prone disease (at risk of leukaemia
and squamous cell carcinoma).
Prognosis
Fanconi anaemia's prognosis is poor; mean survival is
20 years: patients die of bone marrow failure
(infections, haemorrhages), leukaemia, or solid cancer.
It has recently been shown that significant phenotypic
differences were found between the various
complementation groups. In FA group A, patients
homozygous for null mutations had an earlier onset of
anemia and a higher incidence of leukemia than those
with mutations producing an altered protein. Patients
homozygous for null mutations in FANCA are highrisk groups with a poor hematologic outcome and
should be considered as candidates both for frequent
monitoring and early therapeutic intervention.
Cytogenetics
Spontaneously enhanced chromatid-type aberrations
(breaks, gaps, interchanges; increased rate of breaks
compared to control, when induced by specific
clastogens known as DNA cross-linking agents (e.g.
mitomycin C, diepoxybutane).
Biol
Chem.
1999
Nov
Lightfoot J, Alon N, Bosnoyan-Collins L, Buchwald M.
Characterization of regions functional in the nuclear
localization of the Fanconi anemia group A protein. Hum Mol
Genet. 1999 Jun;8(6):1007-15
McMahon LW, Walsh CE, Lambert MW. Human alpha spectrin
II and the Fanconi anemia proteins FANCA and FANCC
interact to form a nuclear complex. J Biol Chem. 1999 Nov
12;274(46):32904-8
Morgan NV, Tipping AJ, Joenje H, Mathew CG. High frequency
of large intragenic deletions in the Fanconi anemia group A
gene. Am J Hum Genet. 1999 Nov;65(5):1330-41
Waisfisz Q, de Winter JP, Kruyt FA, de Groot J, van der Weel
L, Dijkmans LM, Zhi Y, Arwert F, Scheper RJ, Youssoufian H,
Hoatlin ME, Joenje H. A physical complex of the Fanconi
anemia proteins FANCG/XRCC9 and FANCA. Proc Natl Acad
Sci U S A. 1999 Aug 31;96(18):10320-5
Waisfisz Q, Morgan NV, Savino M, de Winter JP, van Berkel
CG, Hoatlin ME, Ianzano L, Gibson RA, Arwert F, Savoia A,
Mathew CG, Pronk JC, Joenje H. Spontaneous functional
correction of homozygous fanconi anaemia alleles reveals
novel mechanistic basis for reverse mosaicism. Nat Genet.
1999 Aug;22(4):379-83
Walsh CE, Yountz MR, Simpson DA. Intracellular localization
of the Fanconi anemia complementation group A protein.
Biochem Biophys Res Commun. 1999 Jun 16;259(3):594-9
Balta G, de Winter JP, Kayserili H, Pronk JC, Joenje H.
Fanconi anemia A due to a novel frameshift mutation in
hotspot motifs: lack of FANCA protein. Hum Mutat. 2000
Jun;15(6):578
References
The Fanconi anaemia/breast cancer consortium.. Positional
cloning of the Fanconi anaemia group A gene. Nat Genet.
1996 Nov;14(3):324-8
de Winter JP, van der Weel L, de Groot J, Stone S, Waisfisz Q,
Arwert F, Scheper RJ, Kruyt FA, Hoatlin ME, Joenje H. The
Fanconi anemia protein FANCF forms a nuclear complex with
FANCA, FANCC and FANCG. Hum Mol Genet. 2000 Nov
1;9(18):2665-74
Lo Ten Foe JR, Rooimans MA, Bosnoyan-Collins L, Alon N,
Wijker M, Parker L, Lightfoot J, Carreau M, Callen DF, Savoia
A, Cheng NC, van Berkel CG, Strunk MH, Gille JJ, Pals G,
Kruyt FA, Pronk JC, Arwert F, Buchwald M, Joenje H.
Expression cloning of a cDNA for the major Fanconi anaemia
gene, FAA. Nat Genet. 1996 Nov;14(3):320-3
Faivre L, Guardiola P, Lewis C, Dokal I, Ebell W, Zatterale A,
Altay C, Poole J, Stones D, Kwee ML, van Weel-Sipman M,
Havenga C, Morgan N, de Winter J, Digweed M, Savoia A,
Pronk J, de Ravel T, Jansen S, Joenje H, Gluckman E,
Mathew CG. Association of complementation group and
mutation type with clinical outcome in fanconi anemia.
European Fanconi Anemia Research Group. Blood. 2000 Dec
15;96(13):4064-70
Kupfer GM, Näf D, Suliman A, Pulsipher M, D'Andrea AD. The
Fanconi anaemia proteins, FAA and FAC, interact to form a
nuclear complex. Nat Genet. 1997 Dec;17(4):487-90
Levran O, Erlich T, Magdalena N, Gregory JJ, Batish SD,
Verlander PC, Auerbach AD. Sequence variation in the
Fanconi anemia gene FAA. Proc Natl Acad Sci U S A. 1997
Nov 25;94(24):13051-6
Garcia-Higuera I, Kuang Y, Denham J, D'Andrea AD. The
fanconi anemia proteins FANCA and FANCG stabilize each
other and promote the nuclear accumulation of the Fanconi
anemia complex. Blood. 2000 Nov 1;96(9):3224-30
Yamashita T, Kupfer GM, Naf D, Suliman A, Joenje H, Asano
S, D'Andrea AD. The fanconi anemia pathway requires FAA
phosphorylation and FAA/FAC nuclear accumulation. Proc Natl
Acad Sci U S A. 1998 Oct 27;95(22):13085-90
Huber PA, Medhurst AL, Youssoufian H, Mathew CG.
Investigation of Fanconi anemia protein interactions by yeast
two-hybrid analysis. Biochem Biophys Res Commun. 2000 Feb
5;268(1):73-7
Garcia-Higuera I, Kuang Y, Näf D, Wasik J, D'Andrea AD.
Fanconi
anemia
proteins
FANCA,
FANCC,
and
FANCG/XRCC9 interact in a functional nuclear complex. Mol
Cell Biol. 1999 Jul;19(7):4866-73
Kuang Y, Garcia-Higuera I, Moran A, Mondoux M, Digweed M,
D'Andrea AD. Carboxy terminal region of the Fanconi anemia
protein, FANCG/XRCC9, is required for functional activity.
Blood. 2000 Sep 1;96(5):1625-32
Kruyt FA, Abou-Zahr F, Mok H, Youssoufian H. Resistance to
mitomycin C requires direct interaction between the Fanconi
anemia proteins FANCA and FANCG in the nucleus through
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
J
van de Vrugt HJ, Cheng NC, de Vries Y, Rooimans MA, de
Groot J, Scheper RJ, Zhi Y, Hoatlin ME, Joenje H, Arwert F.
271
FANCA (Fanconi anaemia complementation group A)
Huret JL
Cloning and characterization of murine fanconi anemia group A
gene: Fanca protein is expressed in lymphoid tissues, testis,
and ovary. Mamm Genome. 2000 Apr;11(4):326-31
Otsuki T, Furukawa Y, Ikeda K, Endo H, Yamashita T,
Shinohara A, Iwamatsu A, Ozawa K, Liu JM. Fanconi anemia
protein, FANCA, associates with BRG1, a component of the
human SWI/SNF complex. Hum Mol Genet. 2001 Nov
1;10(23):2651-60
Wong JC, Alon N, Norga K, Kruyt FA, Youssoufian H,
Buchwald M. Cloning and analysis of the mouse Fanconi
anemia group A cDNA and an overlapping penta zinc finger
cDNA. Genomics. 2000 Aug 1;67(3):273-83
Qiao F, Moss A, Kupfer GM. Fanconi anemia proteins localize
to chromatin and the nuclear matrix in a DNA damage- and cell
cycle-regulated manner. J Biol Chem. 2001 Jun
29;276(26):23391-6
Futaki M, Watanabe S, Kajigaya S, Liu JM. Fanconi anemia
protein, FANCG, is a phosphoprotein and is upregulated with
FANCA after TNF-alpha treatment. Biochem Biophys Res
Commun. 2001 Feb 23;281(2):347-51
Ren J, Youssoufian H. Functional analysis of the putative
peroxidase domain of FANCA, the Fanconi anemia
complementation group A protein. Mol Genet Metab. 2001
Jan;72(1):54-60
Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers
C, Hejna J, Grompe M, D'Andrea AD. Interaction of the
Fanconi anemia proteins and BRCA1 in a common pathway.
Mol Cell. 2001 Feb;7(2):249-62
Yagasaki H, Adachi D, Oda T, Garcia-Higuera I, Tetteh N,
D'Andrea AD, Futaki M, Asano S, Yamashita T. A cytoplasmic
serine protein kinase binds and may regulate the Fanconi
anemia protein FANCA. Blood. 2001 Dec 15;98(13):3650-7
Gregory JJ Jr, Wagner JE, Verlander PC, Levran O, Batish
SD, Eide CR, Steffenhagen A, Hirsch B, Auerbach AD.
Somatic mosaicism in Fanconi anemia: evidence of genotypic
reversion in lymphohematopoietic stem cells. Proc Natl Acad
Sci U S A. 2001 Feb 27;98(5):2532-7
Yamashita T, Nakahata T. Current knowledge on the
pathophysiology of Fanconi anemia: from genes to
phenotypes. Int J Hematol. 2001 Jul;74(1):33-41
Grompe M, D'Andrea A. Fanconi anemia and DNA repair. Hum
Mol Genet. 2001 Oct 1;10(20):2253-9
Callén E, Samper E, Ramírez MJ, Creus A, Marcos R, Ortega
JJ, Olivé T, Badell I, Blasco MA, Surrallés J. Breaks at
telomeres and TRF2-independent end fusions in Fanconi
anemia. Hum Mol Genet. 2002 Feb 15;11(4):439-44
McMahon LW, Sangerman J, Goodman SR, Kumaresan K,
Lambert MW. Human alpha spectrin II and the FANCA,
FANCC, and FANCG proteins bind to DNA containing psoralen
interstrand
cross-links.
Biochemistry.
2001
Jun
19;40(24):7025-34
This article should be referenced as such:
Huret JL. FANCA (Fanconi anaemia complementation group
A). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4):270272.
Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew
CG. Direct interactions of the five known Fanconi anaemia
proteins suggest a common functional pathway. Hum Mol
Genet. 2001 Feb 15;10(4):423-9
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
272
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
FANCC (Fanconi anaemia complementation group
C)
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Genes/FACC101.html
DOI: 10.4267/2042/37892
This article is an update of: Huret JL. FACC (Fanconi anaemia complementation group C). Atlas Genet Cytogenet Oncol
Haematol.1998;2(1):10-11.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Identity
Wide, in particular in the bones; high expression in
proliferating cells, low in differentiated cells.
Other names: FAC
HGNC (Hugo): FANCC
Location: 9q22.3
Local order: next to PTCH and XPAC
Localisation
Cytoplasmic (mostly) and nuclear.
Function
Part of the FA complex with FANCA, FANCE,
FANCF, and FANCG; this complex is only found in
the nucleus.
FANCA and FANCG form a complex in the
cytoplasm, through a N-term FANCA (involving the
nuclear localization signal) - FANCG interaction;
FANCC join the complex; phosphorylation of FANCA
would induce its translocation into the nucleus.This FA
complex translocates into the nucleus, where FANCE
and FANCF are present; FANCE and FANCF join the
complex. The FA complex subsequently interacts with
FANCD2 by monoubiquitination of FANCD2 during S
phase or following DNA damage.
Activated (ubiquinated) FANCD2, downstream in the
FA pathway, will then interact with other proteins
involved in DNA repair, possibly BRCA1; after DNA
repair, FANCD2 return to the non-ubiquinated form.
FANCC may have mutlifunctional roles, in addition to
its involvement in the FA pathway. FANCC binds to
cdc2 (mitotic cyclin-dependent kinase), STAT1,
GRP94 (a chaperon protein), NADPH, and a number of
other proteins; involved in DNA repair and in
suppressing interferon gamma induced cellular
apoptosis.
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular
Cytogenetics.
DNA/RNA
Description
14 exons; spans 80 kb.
Transcription
mRNA of 2.3, 3.2, and 4.6 kb (alternative splicing in 5',
variable 3' untranslated region, exon 13 skipping).
Protein
Description
558 amino acids; 63 kDa.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
273
FANCC (Fanconi anaemia complementation group C)
Huret JL
D'Andrea AD, Grompe M. Molecular biology of Fanconi
anemia: implications for diagnosis and therapy. Blood. 1997
Sep 1;90(5):1725-36
Homology
No known homology.
Garcia-Higuera I, Kuang Y, Näf D, Wasik J, D'Andrea AD.
Fanconi
anemia
proteins
FANCA,
FANCC,
and
FANCG/XRCC9 interact in a functional nuclear complex. Mol
Cell Biol. 1999 Jul;19(7):4866-73
Mutations
Germinal
Most mutations are found in exon1, intron 4, and exon
14.
Faivre L, Guardiola P, Lewis C, Dokal I, Ebell W, Zatterale A,
Altay C, Poole J, Stones D, Kwee ML, van Weel-Sipman M,
Havenga C, Morgan N, de Winter J, Digweed M, Savoia A,
Pronk J, de Ravel T, Jansen S, Joenje H, Gluckman E,
Mathew CG. Association of complementation group and
mutation type with clinical outcome in fanconi anemia.
European Fanconi Anemia Research Group. Blood. 2000 Dec
15;96(13):4064-70
Implicated in
Fanconi anaemia (FA)
FACC is implicated in the FA complementation group
C; it represents about 15% of FA cases.
Disease
Fanconi anaemia is a chromosome instability
syndrome/cancer prone disease (at risk of leukaemia).
Prognosis
Fanconi anaemia's prognosis is poor; mean survival is
16 years: patients die of bone marrow failure
(infections, haemorrhages), leukaemia, or androgen
therapy related liver tumours.
It has recently been shown that significant phenotypic
differences were found between the various
complementation groups. FA group C patients had less
somatic abnormalities. However, there is a certain
clinical heterogeneity.
Cytogenetics
Spontaneous, chromatid/chromosome breaks; increased
rate of breaks compared to control, when induced by
breaking agent.
Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers
C, Hejna J, Grompe M, D'Andrea AD. Interaction of the
Fanconi anemia proteins and BRCA1 in a common pathway.
Mol Cell. 2001 Feb;7(2):249-62
Grompe M, D'Andrea A. Fanconi anemia and DNA repair. Hum
Mol Genet. 2001 Oct 1;10(20):2253-9
Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew
CG. Direct interactions of the five known Fanconi anaemia
proteins suggest a common functional pathway. Hum Mol
Genet. 2001 Feb 15;10(4):423-9
Pang Q, Christianson TA, Keeble W, Diaz J, Faulkner GR,
Reifsteck C, Olson S, Bagby GC. The Fanconi anemia
complementation group C gene product: structural evidence of
multifunctionality. Blood. 2001 Sep 1;98(5):1392-401
Qiao F, Moss A, Kupfer GM. Fanconi anemia proteins localize
to chromatin and the nuclear matrix in a DNA damage- and cell
cycle-regulated manner. J Biol Chem. 2001 Jun
29;276(26):23391-6
Yamashita T, Nakahata T. Current knowledge on the
pathophysiology of Fanconi anemia: from genes to
phenotypes. Int J Hematol. 2001 Jul;74(1):33-41
References
Callén E, Samper E, Ramírez MJ, Creus A, Marcos R, Ortega
JJ, Olivé T, Badell I, Blasco MA, Surrallés J. Breaks at
telomeres and TRF2-independent end fusions in Fanconi
anemia. Hum Mol Genet. 2002 Feb 15;11(4):439-44
Strathdee CA, Gavish H, Shannon WR, Buchwald M. Cloning
of
cDNAs
for
Fanconi's
anaemia
by
functional
complementation. Nature. 1992 Apr 30;356(6372):763-7
This article should be referenced as such:
Gibson RA, Buchwald M, Roberts RG, Mathew CG.
Characterisation of the exon structure of the Fanconi anaemia
group C gene by vectorette PCR. Hum Mol Genet. 1993
Jan;2(1):35-8
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Huret JL. FANCC (Fanconi anaemia complementation group
C). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4):273274.
274
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
FANCD2 (Fanconi anemia, complementation group
D2)
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Genes/FAD.html
DOI: 10.4267/2042/37893
This article is an update of: Huret JL. FAD (Fanconi anaemia group D). Atlas Genet Cytogenet Oncol Haematol.1998;2(3):83.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Function
Identity
The FA complex is comprised of: FANCA, FANCC,
FANCE, FANCF, and FANCG; this complex is only
found in the nucleus.
FANCA and FANCG form a complex in the
cytoplasm, through a N-term FANCA (involving the
nuclear localization signal) - FANCG interaction;
FANCC join the complex; phosphorylation of FANCA
would induce its translocation into the nucleus.This FA
complex translocates into the nucleus, where FANCE
and FANCF are present; FANCE and FANCF join the
complex. The FA complex subsequently interacts with
FANCD2 by monoubiquitination of FANCD2 during S
phase or following DNA damage. Activated
(ubiquinated ) FANCD2 (i.e. FANCD2-L), downstream
in the FA pathway, will then interact with other
proteins involved in DNA repair, possibly BRCA1;
after DNA repair, FANCD2 return to the nonubiquinated form (FANCD2-S).
FANCD2co-localizes with BRCA1 in DNA damagedinduced loci and in the synaptonemal complex of
meotic chromosomes as well.
Other names: FAD; FAD2; FACD; FANCD
HGNC (Hugo): FANCD2
Location: 3p25-26
Local order: not far from XPC, in 3p25.
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular
Cytogenetics.
DNA/RNA
Description
44 exons; 4356 bp open reading frame; the first exon is
non-coding.
Protein
Homology
Description
Significant homologies can be found with proteins
from various species.
1452 amino acids; 155 kDa (FANCD2-S isoform, for
short), and 162 kDa (FANCD2-L isoform, for long) by
ubiquitin addition.
Implicated in
Expression
Fanconi anaemia (FA)
Weak.
FANCD2 is implicated in the FA complementation
group D, a heterogeneous group, with at least 2 genes:
FANCD2, and a yet undiscovered FANCD1. FA
complementation group D represents about 1% of FA
Localisation
Nucleus.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
275
FANCD2 (Fanconi anemia, complementation group D2)
Huret JL
Hejna JA, Timmers CD, Reifsteck C, Bruun DA, Lucas LW,
Jakobs PM, Toth-Fejel S, Unsworth N, Clemens SL, Garcia
DK, Naylor SL, Thayer MJ, Olson SB, Grompe M, Moses RE.
Localization of the Fanconi anemia complementation group D
gene to a 200-kb region on chromosome 3p25.3. Am J Hum
Genet. 2000 May;66(5):1540-51
cases. In FA complementation group D patients, the FA
complex is normal, in contrast with results found in
group A, B (with a yet unknown gene), C, E, F, and G
patients.
Disease
Fanconi anaemia is a chromosome instability
syndrome/cancer prone disease (at risk of leukaemia
and squamous cell carcinoma).
Prognosis
Fanconi anaemia's prognosis is poor; mean survival is
20 years: patients die of bone marrow failure
(infections, haemorrhages), leukaemia, or solid cancer.
It has recently been shown that significant phenotypic
differences were found between the various
complementation groups. Patients from the rare groups
FA-D, FA-E, and FA-F had somatic abnormalities
more frequently.
Cytogenetics
Spontaneously enhanced chromatid-type aberrations
(breaks, gaps, interchanges; increased rate of breaks
compared to control, when induced by specific
clastogens known as DNA cross-linking agents (e.g.
mitomycin C, diepoxybutane).
Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers
C, Hejna J, Grompe M, D'Andrea AD. Interaction of the
Fanconi anemia proteins and BRCA1 in a common pathway.
Mol Cell. 2001 Feb;7(2):249-62
Grompe M, D'Andrea A. Fanconi anemia and DNA repair. Hum
Mol Genet. 2001 Oct 1;10(20):2253-9
Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew
CG. Direct interactions of the five known Fanconi anaemia
proteins suggest a common functional pathway. Hum Mol
Genet. 2001 Feb 15;10(4):423-9
Qiao F, Moss A, Kupfer GM. Fanconi anemia proteins localize
to chromatin and the nuclear matrix in a DNA damage- and cell
cycle-regulated manner. J Biol Chem. 2001 Jun
29;276(26):23391-6
Timmers C, Taniguchi T, Hejna J, Reifsteck C, Lucas L, Bruun
D, Thayer M, Cox B, Olson S, D'Andrea AD, Moses R, Grompe
M. Positional cloning of a novel Fanconi anemia gene,
FANCD2. Mol Cell. 2001 Feb;7(2):241-8
Wilson JB, Johnson MA, Stuckert AP, Trueman KL, May S,
Bryant PE, Meyn RE, D'Andrea AD, Jones NJ. The Chinese
hamster FANCG/XRCC9 mutant NM3 fails to express the
monoubiquitinated form of the FANCD2 protein, is
hypersensitive to a range of DNA damaging agents and
exhibits a normal level of spontaneous sister chromatid
exchange. Carcinogenesis. 2001 Dec;22(12):1939-46
References
Whitney M, Thayer M, Reifsteck C, Olson S, Smith L, Jakobs
PM, Leach R, Naylor S, Joenje H, Grompe M. Microcell
mediated chromosome transfer maps the Fanconi anaemia
group D gene to chromosome 3p. Nat Genet. 1995
Nov;11(3):341-3
Yamashita T, Nakahata T. Current knowledge on the
pathophysiology of Fanconi anemia: from genes to
phenotypes. Int J Hematol. 2001 Jul;74(1):33-41
D'Andrea AD, Grompe M. Molecular biology of Fanconi
anemia: implications for diagnosis and therapy. Blood. 1997
Sep 1;90(5):1725-36
Yang Y, Kuang Y, Montes De Oca R, Hays T, Moreau L, Lu N,
Seed B, D'Andrea AD. Targeted disruption of the murine
Fanconi anemia gene, Fancg/Xrcc9. Blood. 2001 Dec
1;98(12):3435-40
Garcia-Higuera I, Kuang Y, Näf D, Wasik J, D'Andrea AD.
Fanconi
anemia
proteins
FANCA,
FANCC,
and
FANCG/XRCC9 interact in a functional nuclear complex. Mol
Cell Biol. 1999 Jul;19(7):4866-73
Callén E, Samper E, Ramírez MJ, Creus A, Marcos R, Ortega
JJ, Olivé T, Badell I, Blasco MA, Surrallés J. Breaks at
telomeres and TRF2-independent end fusions in Fanconi
anemia. Hum Mol Genet. 2002 Feb 15;11(4):439-44
Faivre L, Guardiola P, Lewis C, Dokal I, Ebell W, Zatterale A,
Altay C, Poole J, Stones D, Kwee ML, van Weel-Sipman M,
Havenga C, Morgan N, de Winter J, Digweed M, Savoia A,
Pronk J, de Ravel T, Jansen S, Joenje H, Gluckman E,
Mathew CG. Association of complementation group and
mutation type with clinical outcome in fanconi anemia.
European Fanconi Anemia Research Group. Blood. 2000 Dec
15;96(13):4064-70
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
This article should be referenced as such:
Huret JL. FANCD2 (Fanconi anemia, complementation group
D2). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4):275276.
276
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
FANCE (Fanconi anemia, complementation group
E)
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Genes/FANCEID293.html
DOI: 10.4267/2042/37894
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
cytoplasm, through a N-term FANCA (involving the
nuclear localization signal) - FANCG interaction;
FANCC join the complex; phosphorylation of FANCA
would induce its translocation into the nucleus.This FA
complex translocates into the nucleus, where FANCE
and FANCF are present; FANCE and FANCF join the
complex. The FA complex subsequently interacts with
FANCD2 by monoubiquitination of FANCD2 during S
phase or following DNA damage. Activated
(ubiquinated) FANCD2, downstream in the FA
pathway, will then interact with other proteins involved
in DNA repair, possibly BRCA1; after DNA repair,
FANCD2 return to the non-ubiquinated form.
Identity
Other names: FACE; FAE
HGNC (Hugo): FANCE
Location: 6p21
Local order: located between the 60S ribosomal
protein RPL10Aand a ZNF127 like protein.
Homology
No known homology.
Implicated in
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular
Cytogenetics.
Fanconi anaemia (FA)
DNA/RNA
FANCE is implicated in the FA complementation
group E; it represents about 2% of FA cases.
Disease
Fanconi anaemia is a chromosome instability
syndrome/cancer prone disease (at risk of leukaemia).
Prognosis
Fanconi anaemia's prognosis is poor; mean survival is
20 years (depending on mutation, treatment): patients
die of bone marrow failure (infections, haemorrhages),
leukaemia, or androgen therapy related liver tumours.
It has recently been shown that significant phenotypic
differences were found between the various
complementation groups. Patients from the rare groups
FA-D, FA-E, and FA-F had somatic abnormalities
more frequently.
Description
The gene spans 15 kb and contains 10 exons; 1611 bp
open reading frame.
Protein
Description
536 amino acids, 60 kDa; contains two potential
nuclear localization signals.
Function
Part of the FA complex with FANCA, FANCC,
FANCF, and FANCG. ; this complex is only found in
the nucleus.
FANCA and FANCG form a complex in the
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
277
FANCE (Fanconi anemia, complementation group E)
Huret JL
Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers
C, Hejna J, Grompe M, D'Andrea AD. Interaction of the
Fanconi anemia proteins and BRCA1 in a common pathway.
Mol Cell. 2001 Feb;7(2):249-62
Cytogenetics
Spontaneous, chromatid/chromosome breaks; increased
rate of breaks compared to control, when induced by
breaking agent.
Grompe M, D'Andrea A. Fanconi anemia and DNA repair. Hum
Mol Genet. 2001 Oct 1;10(20):2253-9
References
Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew
CG. Direct interactions of the five known Fanconi anaemia
proteins suggest a common functional pathway. Hum Mol
Genet. 2001 Feb 15;10(4):423-9
Garcia-Higuera I, Kuang Y, Näf D, Wasik J, D'Andrea AD.
Fanconi
anemia
proteins
FANCA,
FANCC,
and
FANCG/XRCC9 interact in a functional nuclear complex. Mol
Cell Biol. 1999 Jul;19(7):4866-73
Qiao F, Moss A, Kupfer GM. Fanconi anemia proteins localize
to chromatin and the nuclear matrix in a DNA damage- and cell
cycle-regulated manner. J Biol Chem. 2001 Jun
29;276(26):23391-6
de Winter JP, Léveillé F, van Berkel CG, Rooimans MA, van
Der Weel L, Steltenpool J, Demuth I, Morgan NV, Alon N,
Bosnoyan-Collins L, Lightfoot J, Leegwater PA, Waisfisz Q,
Komatsu K, Arwert F, Pronk JC, Mathew CG, Digweed M,
Buchwald M, Joenje H. Isolation of a cDNA representing the
Fanconi anemia complementation group E gene. Am J Hum
Genet. 2000 Nov;67(5):1306-8
Yamashita T, Nakahata T. Current knowledge on the
pathophysiology of Fanconi anemia: from genes to
phenotypes. Int J Hematol. 2001 Jul;74(1):33-41
Callén E, Samper E, Ramírez MJ, Creus A, Marcos R, Ortega
JJ, Olivé T, Badell I, Blasco MA, Surrallés J. Breaks at
telomeres and TRF2-independent end fusions in Fanconi
anemia. Hum Mol Genet. 2002 Feb 15;11(4):439-44
Faivre L, Guardiola P, Lewis C, Dokal I, Ebell W, Zatterale A,
Altay C, Poole J, Stones D, Kwee ML, van Weel-Sipman M,
Havenga C, Morgan N, de Winter J, Digweed M, Savoia A,
Pronk J, de Ravel T, Jansen S, Joenje H, Gluckman E,
Mathew CG. Association of complementation group and
mutation type with clinical outcome in fanconi anemia.
European Fanconi Anemia Research Group. Blood. 2000 Dec
15;96(13):4064-70
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
This article should be referenced as such:
Huret JL. FANCE (Fanconi anemia, complementation group
E). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4):277278.
278
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
FANCF (Fanconi anemia, complementation group
F)
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Genes/FANCFID294.html
DOI: 10.4267/2042/37895
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
FANCA and FANCG form a complex in the
cytoplasm, through a N-term FANCA (involving the
nuclear localization signal) - FANCG interaction;
FANCC join the complex; phosphorylation of FANCA
would induce its translocation into the nucleus.This FA
complex translocates into the nucleus, where FANCE
and FANCF are present; FANCE and FANCF join the
complex. The FA complex subsequently interacts with
FANCD2 by monoubiquitination of FANCD2 during S
phase or following DNA damage. Activated
(ubiquinated) FANCD2, downstream in the FA
pathway, will then interact with other proteins involved
in DNA repair, possibly BRCA1; after DNA repair,
FANCD2 return to the non-ubiquinated form.
Identity
Other names: FAF
HGNC (Hugo): FANCF
Location: 11p15
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular
Cytogenetics.
Homology
DNA/RNA
ROM (prokaryote).
Description
Implicated in
1 exon; 1124 bp open reading frame.
Fanconi anaemia (FA)
Protein
FANCF is implicated in the FA complementation
group F; it represents about 2-3% of FA cases.
Disease
Fanconi anaemia is a chromosome instability
syndrome/cancer prone disease (at risk of leukaemia
and squamous cell carcinoma).
Prognosis
Fanconi anaemia's prognosis is poor; mean survival is
20 years: patients die of bone marrow failure
(infections, haemorrhages), leukaemia, or solid cancer.
It has recently been shown that significant phenotypic
differences were found between the various
complementation groups. Patients from the rare groups
Description
374 amino acids ; 42 kDa.
Expression
Weak.
Localisation
Predominantly nuclear.
Function
Part of the FA complex with FANCA, FANCC,
FANCE, and FANCG; this complex is only found in
the nucleus.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
279
FANCF (Fanconi anemia, complementation group F)
Huret JL
Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers
C, Hejna J, Grompe M, D'Andrea AD. Interaction of the
Fanconi anemia proteins and BRCA1 in a common pathway.
Mol Cell. 2001 Feb;7(2):249-62
FA-D, FA-E, and FA-F had somatic abnormalities
more frequently.
Cytogenetics
Spontaneously enhanced chromatid-type aberrations
(breaks, gaps, interchanges; increased rate of breaks
compared to control, when induced by specific
clastogens known as DNA cross-linking agents (e.g.
mitomycin C, diepoxybutane).
Grompe M, D'Andrea A. Fanconi anemia and DNA repair. Hum
Mol Genet. 2001 Oct 1;10(20):2253-9
Holmes RK, Harutyunyan K, Shah M, Joenje H, Youssoufian
H. Correction of cross-linker sensitivity of Fanconi anemia
group F cells by CD33-mediated protein transfer. Blood. 2001
Dec 15;98(13):3817-22
References
Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew
CG. Direct interactions of the five known Fanconi anaemia
proteins suggest a common functional pathway. Hum Mol
Genet. 2001 Feb 15;10(4):423-9
Garcia-Higuera I, Kuang Y, Näf D, Wasik J, D'Andrea AD.
Fanconi
anemia
proteins
FANCA,
FANCC,
and
FANCG/XRCC9 interact in a functional nuclear complex. Mol
Cell Biol. 1999 Jul;19(7):4866-73
Qiao F, Moss A, Kupfer GM. Fanconi anemia proteins localize
to chromatin and the nuclear matrix in a DNA damage- and cell
cycle-regulated manner. J Biol Chem. 2001 Jun
29;276(26):23391-6
de Winter JP, Rooimans MA, van Der Weel L, van Berkel CG,
Alon N, Bosnoyan-Collins L, de Groot J, Zhi Y, Waisfisz Q,
Pronk JC, Arwert F, Mathew CG, Scheper RJ, Hoatlin ME,
Buchwald M, Joenje H. The Fanconi anaemia gene FANCF
encodes a novel protein with homology to ROM. Nat Genet.
2000 Jan;24(1):15-6
Siddique MA, Nakanishi K, Taniguchi T, Grompe M, D'Andrea
AD. Function of the Fanconi anemia pathway in Fanconi
anemia complementation group F and D1 cells. Exp Hematol.
2001 Dec;29(12):1448-55
de Winter JP, van der Weel L, de Groot J, Stone S, Waisfisz Q,
Arwert F, Scheper RJ, Kruyt FA, Hoatlin ME, Joenje H. The
Fanconi anemia protein FANCF forms a nuclear complex with
FANCA, FANCC and FANCG. Hum Mol Genet. 2000 Nov
1;9(18):2665-74
Yamashita T, Nakahata T. Current knowledge on the
pathophysiology of Fanconi anemia: from genes to
phenotypes. Int J Hematol. 2001 Jul;74(1):33-41
Callén E, Samper E, Ramírez MJ, Creus A, Marcos R, Ortega
JJ, Olivé T, Badell I, Blasco MA, Surrallés J. Breaks at
telomeres and TRF2-independent end fusions in Fanconi
anemia. Hum Mol Genet. 2002 Feb 15;11(4):439-44
Faivre L, Guardiola P, Lewis C, Dokal I, Ebell W, Zatterale A,
Altay C, Poole J, Stones D, Kwee ML, van Weel-Sipman M,
Havenga C, Morgan N, de Winter J, Digweed M, Savoia A,
Pronk J, de Ravel T, Jansen S, Joenje H, Gluckman E,
Mathew CG. Association of complementation group and
mutation type with clinical outcome in fanconi anemia.
European Fanconi Anemia Research Group. Blood. 2000 Dec
15;96(13):4064-70
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
This article should be referenced as such:
Huret JL. FANCF (Fanconi anemia, complementation group F).
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4):279-280.
280
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
FANCG (Fanconi anemia, complementation group
G)
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Genes/FANCGID295.html
DOI: 10.4267/2042/37896
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Function
Identity
Description
Part of the FA complex with FANCA, FANCC,
FANCE, and FANCF; this complex is only found in the
nucleus.
FANCA and FANCG form a complex in the
cytoplasm, through a N-term FANCA (involving the
nuclear localization signal) - FANCG interaction;
FANCC join the complex; phosphorylation of FANCA
would induce its translocation into the nucleus.This FA
complex translocates into the nucleus, where FANCE
and FANCF are present; FANCE and FANCF join the
complex. The FA complex subsequently interacts with
FANCD2 by monoubiquitination of FANCD2 during S
phase or following DNA damage. Activated
(ubiquinated) FANCD2, downstream in the FA
pathway, will then interact with other proteins involved
in DNA repair, possibly BRCA1; after DNA repair,
FANCD2 return to the non-ubiquinated form.
14 exons; 1869 bp open reading frame.
Homology
Transcription
No known homology.
2.2 and 2.5 kb.
Mutations
Protein
Germinal
Description
Wide range of mutations (splice, nonsense, missense).
622 amino acids, 69 kDa; contains a leucine zipper; can
be phosphorylated.
Implicated in
Expression
Fanconi anaemia (FA)
Weak; testis, thymus, lymphoblasts.
FANCG is implicated in the FA complementation
group G; it represents about 10% of FA cases.
Disease
Fanconi anaemia is a chromosome instability
syndrome/cancer prone disease (at risk of leukaemia
and squamous cell carcinoma).
Other names: FAG; XRCC9
complementing defective repair 9)
HGNC (Hugo): FANCG
Location: 9p13
(X-ray
repair
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular
Cytogenetics.
DNA/RNA
Localisation
Predominantly nuclear.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
281
FANCG (Fanconi anemia, complementation group G)
Huret JL
Prognosis
Fanconi anaemia's prognosis is poor; mean survival is
20 years: patients die of bone marrow failure
(infections, haemorrhages), leukaemia, or solid cancer.
It has recently been shown that significant phenotypic
differences were found between the various
complementation groups. FA group G patients had
more severe cytopenia and a higher incidence of
leukemia. FA group G patients are high-risk groups
with a poor hematologic outcome and should be
considered as candidates both for frequent monitoring
and early therapeutic intervention.
Cytogenetics
Spontaneously enhanced chromatid-type aberrations
(breaks, gaps, interchanges; increased rate of breaks
compared to control, when induced by specific
clastogens known as DNA cross-linking agents (e.g.
mitomycin C, diepoxybutane).
protein, FANCG/XRCC9, is required for functional activity.
Blood. 2000 Sep 1;96(5):1625-32
References
Qiao F, Moss A, Kupfer GM. Fanconi anemia proteins localize
to chromatin and the nuclear matrix in a DNA damage- and cell
cycle-regulated manner. J Biol Chem. 2001 Jun
29;276(26):23391-6
Futaki M, Watanabe S, Kajigaya S, Liu JM. Fanconi anemia
protein, FANCG, is a phosphoprotein and is upregulated with
FANCA after TNF-alpha treatment. Biochem Biophys Res
Commun. 2001 Feb 23;281(2):347-51
Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers
C, Hejna J, Grompe M, D'Andrea AD. Interaction of the
Fanconi anemia proteins and BRCA1 in a common pathway.
Mol Cell. 2001 Feb;7(2):249-62
Grompe M, D'Andrea A. Fanconi anemia and DNA repair. Hum
Mol Genet. 2001 Oct 1;10(20):2253-9
Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew
CG. Direct interactions of the five known Fanconi anaemia
proteins suggest a common functional pathway. Hum Mol
Genet. 2001 Feb 15;10(4):423-9
Nakanishi K, Moran A, Hays T, Kuang Y, Fox E, Garneau D,
Montes de Oca R, Grompe M, D'Andrea AD. Functional
analysis of patient-derived mutations in the Fanconi anemia
gene, FANCG/XRCC9. Exp Hematol. 2001 Jul;29(7):842-9
Liu N, Lamerdin JE, Tucker JD, Zhou ZQ, Walter CA, Albala
JS, Busch DB, Thompson LH. The human XRCC9 gene
corrects chromosomal instability and mutagen sensitivities in
CHO UV40 cells. Proc Natl Acad Sci U S A. 1997 Aug
19;94(17):9232-7
Wilson JB, Johnson MA, Stuckert AP, Trueman KL, May S,
Bryant PE, Meyn RE, D'Andrea AD, Jones NJ. The Chinese
hamster FANCG/XRCC9 mutant NM3 fails to express the
monoubiquitinated form of the FANCD2 protein, is
hypersensitive to a range of DNA damaging agents and
exhibits a normal level of spontaneous sister chromatid
exchange. Carcinogenesis. 2001 Dec;22(12):1939-46
de Winter JP, Waisfisz Q, Rooimans MA, van Berkel CG,
Bosnoyan-Collins L, Alon N, Carreau M, Bender O, Demuth I,
Schindler D, Pronk JC, Arwert F, Hoehn H, Digweed M,
Buchwald M, Joenje H. The Fanconi anaemia group G gene
FANCG is identical with XRCC9. Nat Genet. 1998
Nov;20(3):281-3
Yamashita T, Nakahata T. Current knowledge on the
pathophysiology of Fanconi anemia: from genes to
phenotypes. Int J Hematol. 2001 Jul;74(1):33-41
Garcia-Higuera I, Kuang Y, Näf D, Wasik J, D'Andrea AD.
Fanconi
anemia
proteins
FANCA,
FANCC,
and
FANCG/XRCC9 interact in a functional nuclear complex. Mol
Cell Biol. 1999 Jul;19(7):4866-73
Yang Y, Kuang Y, Montes De Oca R, Hays T, Moreau L, Lu N,
Seed B, D'Andrea AD. Targeted disruption of the murine
Fanconi anemia gene, Fancg/Xrcc9. Blood. 2001 Dec
1;98(12):3435-40
Waisfisz Q, de Winter JP, Kruyt FA, de Groot J, van der Weel
L, Dijkmans LM, Zhi Y, Arwert F, Scheper RJ, Youssoufian H,
Hoatlin ME, Joenje H. A physical complex of the Fanconi
anemia proteins FANCG/XRCC9 and FANCA. Proc Natl Acad
Sci U S A. 1999 Aug 31;96(18):10320-5
Callén E, Samper E, Ramírez MJ, Creus A, Marcos R, Ortega
JJ, Olivé T, Badell I, Blasco MA, Surrallés J. Breaks at
telomeres and TRF2-independent end fusions in Fanconi
anemia. Hum Mol Genet. 2002 Feb 15;11(4):439-44
Demuth I, Wlodarski M, Tipping AJ, Morgan NV, de Winter JP,
Thiel M, Gräsl S, Schindler D, D'Andrea AD, Altay C, Kayserili
H, Zatterale A, Kunze J, Ebell W, Mathew CG, Joenje H,
Sperling K, Digweed M. Spectrum of mutations in the Fanconi
anaemia group G gene, FANCG/XRCC9. Eur J Hum Genet.
2000 Nov;8(11):861-8
Futaki M, Igarashi T, Watanabe S, Kajigaya S, Tatsuguchi A,
Wang J, Liu JM. The FANCG Fanconi anemia protein interacts
with CYP2E1: possible role in protection against oxidative DNA
damage. Carcinogenesis. 2002 Jan;23(1):67-72
Koomen M, Cheng NC, van de Vrugt HJ, Godthelp BC, van der
Valk MA, Oostra AB, Zdzienicka MZ, Joenje H, Arwert F.
Reduced fertility and hypersensitivity to mitomycin C
characterize Fancg/Xrcc9 null mice. Hum Mol Genet. 2002 Feb
1;11(3):273-81
Faivre L, Guardiola P, Lewis C, Dokal I, Ebell W, Zatterale A,
Altay C, Poole J, Stones D, Kwee ML, van Weel-Sipman M,
Havenga C, Morgan N, de Winter J, Digweed M, Savoia A,
Pronk J, de Ravel T, Jansen S, Joenje H, Gluckman E,
Mathew CG. Association of complementation group and
mutation type with clinical outcome in fanconi anemia.
European Fanconi Anemia Research Group. Blood. 2000 Dec
15;96(13):4064-70
This article should be referenced as such:
Huret JL. FANCG (Fanconi anemia, complementation group
G). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4):281282.
Kuang Y, Garcia-Higuera I, Moran A, Mondoux M, Digweed M,
D'Andrea AD. Carboxy terminal region of the Fanconi anemia
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
282
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
PLAG1 (Pleomorphic adenoma gene 1)
David Gisselsson
Department of Clinical Genetics, Lund University Hospital, 221 85 Lund, Sweden (DG)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Genes/PLAG1ID74.html
DOI: 10.4267/2042/37897
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Localisation
Identity
Nuclear.
HGNC (Hugo): PLAG1
Location: 8q12
Local order: (316 cR / 86 Mb from 8pter)
Function
One of the N-terminal nuclear localisation signals
(NLS1) interacts with karyopherin a2, which escorts
proteins into the nucleus. Three of the seven Zn-finger
domains are responsible for interaction with DNA and
PLAG1 specifically activates transcription from its
consensus binding site. Potential PLAG1 binding sites
have been found in the promoter of IGF2.
DNA/RNA
Description
7313 bp, 5 exons, 4 introns.
Transcription
Homology
At least two splicing variants, including and excluding
the second exon.
Mouse and rat Plag1.
Mutations
Protein
Somatic
Description
Involved in chromosome rearrangements in epithelial
and mesenchymal tumours. These are typically
complex structural abnormalities, resulting in an
exchange of regulatory elements and abnormal
expression of PLAG1.
500 amino acids with at least three functional regions:
1. Two N-terminal nuclear localisation signals, 2.
Seven canonical zinc-finger domains, 3. A serine rich
C-terminus.
Expression
Heart, placenta, spleen, prostate, testis, ovary, small
intestine, several tumours.
Schematic view of the gene with approximate sizes of introns (kb) and exons (bp); the coding region (violet) translates into a 500 amino
acid product with three functional subunits.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
283
PLAG1 (Pleomorphic adenoma gene 1)
Gisselsson D
Implicated in
References
Pleomorphic adenoma of the salivary
gland
Kas K, Röijer E, Voz M, Meyen E, Stenman G, Van de Ven
WJ. A 2-Mb YAC contig and physical map covering the
chromosome 8q12 breakpoint cluster region in pleomorphic
adenomas of the salivary glands. Genomics. 1997 Aug
1;43(3):349-58
Disease
Benign epithelial tumour.
Prognosis
Recovery after surgical removal.
Cytogenetics
The most common breakpoints are 3p21, 8q12, and
12q15.
Hybrid/Mutated gene
The following translocations have been reported to
result in hybrid genes involving PLAG1:
- t(3;8)(p21;q12): CTNNB1 CTNNB1/PLAG1
- t(5;8)(p13;q12): LIFR/PLAG1
Also, rearrangements between PLAG1 and TCEA1
have been detected in cases with normal karyotypes.
Abnormal protein
Fusions occur in the 5' regulatory regions, leading to
promoter swapping and activation of PLAG1
expression while preserving coding sequences.
Kas K, Voz ML, Röijer E, Aström AK, Meyen E, Stenman G,
Van de Ven WJ. Promoter swapping between the genes for a
novel zinc finger protein and beta-catenin in pleiomorphic
adenomas with t(3;8)(p21;q12) translocations. Nat Genet. 1997
Feb;15(2):170-4
Kas K, Voz ML, Hensen K, Meyen E, Van de Ven WJ.
Transcriptional activation capacity of the novel PLAG family of
zinc finger proteins. J Biol Chem. 1998 Sep 4;273(36):2302632
Voz ML, Aström AK, Kas K, Mark J, Stenman G, Van de Ven
WJ. The recurrent translocation t(5;8)(p13;q12) in pleomorphic
adenomas results in upregulation of PLAG1 gene expression
under control of the LIFR promoter. Oncogene. 1998
Mar;16(11):1409-16
Aström AK, Voz ML, Kas K, Röijer E, Wedell B, Mandahl N,
Van de Ven W, Mark J, Stenman G. Conserved mechanism of
PLAG1 activation in salivary gland tumors with and without
chromosome 8q12 abnormalities: identification of SII as a new
fusion partner gene. Cancer Res. 1999 Feb 15;59(4):918-23
Queimado L, Lopes C, Du F, Martins C, Bowcock AM, Soares
J, Lovett M. Pleomorphic adenoma gene 1 is expressed in
cultured benign and malignant salivary gland tumor cells. Lab
Invest. 1999 May;79(5):583-9
Carcinoma ex pleomorphic adenoma
Disease
Malignant epithelial tumour arising from pleomorphic
adenoma.
Prognosis
30% five-year survival.
Cytogenetics
Complex karyotype including t(3;8)(p23;q12).
Hybrid/Mutated gene
Intragenic PLAG1 rearrangements demonstrated by
fluorescence in situ hybridisation.
Röijer E, Kas K, Behrendt M, Van de Ven W, Stenman G.
Fluorescence in situ hybridization mapping of breakpoints in
pleomorphic adenomas with 8q12-13 abnormalities identifies a
subgroup of tumors without PLAG1 involvement. Genes
Chromosomes Cancer. 1999 Jan;24(1):78-82
Astrom A, D'Amore ES, Sainati L, Panarello C, Morerio C,
Mark J, Stenman G. Evidence of involvement of the PLAG1
gene in lipoblastomas. Int J Oncol. 2000 Jun;16(6):1107-10
Hibbard MK, Kozakewich HP, Dal Cin P, Sciot R, Tan X, Xiao
S, Fletcher JA. PLAG1 fusion oncogenes in lipoblastoma.
Cancer Res. 2000 Sep 1;60(17):4869-72
Lipoblastoma
Voz ML, Agten NS, Van de Ven WJ, Kas K. PLAG1, the main
translocation target in pleomorphic adenoma of the salivary
glands, is a positive regulator of IGF-II. Cancer Res. 2000 Jan
1;60(1):106-13
Disease
Benign fat-forming tumour of childhood.
Prognosis
Recovery after surgical removal.
Cytogenetics
Structural abnormalities involving 8q11-13.
Hybrid/Mutated gene
The following rearrangements have been reported to
result in hybrid genes involving PLAG1:
- del(8)(q12q24), r(8): HAS2/PLAG1
- t(7;8)(p22;q13): COL1A2/HAS2
Abnormal protein
Fusions occur in the 5' regulatory regions, leading
promoter swapping and activation of PLAG1
expression while preserving coding sequences.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Voz ML, Van de Ven WJ, Kas K. First insights into the
molecular basis of pleomorphic adenomas of the salivary
glands. Adv Dent Res. 2000 Dec;14:81-3
Debiec-Rychter M, Van Valckenborgh I, Van den Broeck C,
Hagemeijer A, Van de Ven WJ, Kas K, Van Damme B, Voz
ML. Histologic localization of PLAG1 (pleomorphic adenoma
gene 1) in pleomorphic adenoma of the salivary gland:
cytogenetic evidence of common origin of phenotypically
diverse cells. Lab Invest. 2001 Sep;81(9):1289-97
Gisselsson D, Hibbard MK, Dal Cin P, Sciot R, Hsi BL,
Kozakewich HP, Fletcher JA. PLAG1 alterations in
lipoblastoma: involvement in varied mesenchymal cell types
and evidence for alternative oncogenic mechanisms. Am J
Pathol. 2001 Sep;159(3):955-62
284
PLAG1 (Pleomorphic adenoma gene 1)
Gisselsson D
Jin C, Martins C, Jin Y, Wiegant J, Wennerberg J, Dictor M,
Gisselsson D, Strömbeck B, Fonseca I, Mitelman F, Tanke HJ,
Höglund M, Mertens F. Characterization of chromosome
aberrations in salivary gland tumors by FISH, including
multicolor COBRA-FISH. Genes Chromosomes Cancer. 2001
Feb;30(2):161-7
Enlund F, Nordkvist A, Sahlin P, Mark J, Stenman G.
Expression of PLAG1 and HMGIC proteins and fusion
transcripts in radiation-associated pleomorphic adenomas. Int
J Oncol. 2002 Apr;20(4):713-6
Hensen K, Van Valckenborgh IC, Kas K, Van de Ven WJ, Voz
ML. The tumorigenic diversity of the three PLAG family
members is associated with different DNA binding capacities.
Cancer Res. 2002 Mar 1;62(5):1510-7
Szpirer C, Kas K, Laes JF, Rivière M, Van Vooren P, Szpirer J.
Assignment of the rat pleiomorphic adenoma genes (Plag1,
Plagl1, Plagl2) by in situ hybridization and radiation hybrid
mapping. Cytogenet Cell Genet. 2001;94(1-2):94-5
This article should be referenced as such:
Braem CV, Kas K, Meyen E, Debiec-Rychter M, Van De Ven
WJ, Voz ML. Identification of a karyopherin alpha 2 recognition
site in PLAG1, which functions as a nuclear localization signal.
J Biol Chem. 2002 May 31;277(22):19673-8
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Gisselsson D. PLAG1 (Pleomorphic adenoma gene 1). Atlas
Genet Cytogenet Oncol Haematol. 2002; 6(4):283-285.
285
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
Angioimmunoblastic T-cell lymphoma
Antonio Cuneo, Gianluigi Castoldi
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC, GLC)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/AngioimmunoblID2124.html
DOI: 10.4267/2042/37898
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
small-to-large cells resembling immunoblasts and
atypical clear cells with round nucleus and abundant
pale cytoplasm. The latter cells may occur in small
aggregates or sheets.
Identity
Alias
Angioimmunoblastic
disprotidemia.
lymphadenopathy
with
Treatment
Some patients respond to steroids; in steroidunresponsive patients multiagent chemotherapy usually
produces short lasting responses.
Clinics and pathology
Phenotype/cell stem origin
Evolution
The lymphoma cell is a peripheral T lymphocyte in
various stages of differentiation. The neoplastic clone
expresses T-cell antigens and is usually CD4+. The
malignant T-cells are believed to secrete cytokines
responsible for the polyclonal B-cell hyperplasia
observed in involved nodes. Clonality studies
demonstrated a monoclonal rearrangement of the bchain of the T-cell receptor (TCR) in the majority of
cases. In some cases clonality could not be
demonstrated. This led some authors to postulate the
existence of at least two types of AILD, namely a
reactive and benign type and a lymphomatous form.
Few patients present spontaneous or steroid-induced
remission; the majority of cases feature an aggressive
disease with short survival despite chemotherapy. Most
patients die with infection and active disease.
Prognosis
Median survival is about 1-3 years.
Cytogenetics
Note
A mixture of normal and abnormal cells is usually seen
in the vast majority of cases. The cytogenetic picture at
disease presentation may be normal in some cases
which may develop clonal abnormalites during the
course of the disease. The following karyotype pattern
can be found.
Etiology
The disease is rare.
Clinics
The disease preferentially affects elderly males (maleto-female ratio 3:1, median age around 60 years). Most
patients present with generalized lymphadenopathy,
hepatosplenomegaly, skin rash and general symptoms
(fever,
weight
loss).
Polyclonal
hypergammaglobulinemia is a common finding.
Cytogenetics morphological
Clonal abnormalities defining a stemline, with one or
more sidelines (approximately 30-50% of the cases).
Normal karyotype (10-30% of the cases).
Single cells with unrelated chromosome anomalies (1020%).
Unrelated clones with aberrant karyotypes, each
carrying single unrelated additional anomalies (1020%).
Recurrent chromosome changes in those cases with an
abnormal clone include trisomy 3, trisomy 5 and
Pathology
The lymph node architecture is effaced and no reactive
germinal centres are usually observed. The infiltrate
may involve the perinodal fat. There is a proliferation
of high endothelial venules with clusters of follicular
dendritic cells. The lymphoid infiltrate consists of
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
286
Angioimmunoblastic T-cell lymphoma
Cuneo A, Castoldi GL
Schlegelberger B, Feller A, Gödde E, Grote W, Lennert K.
Stepwise development of chromosomal abnormalities in
angioimmunoblastic
lymphadenopathy.
Cancer
Genet
Cytogenet. 1990 Nov 1;50(1):15-29
trisomy X A 14q+ chromosome is a recurrent structural
defect. Recurrent breakpoints include 1p31-32; 3p2425; 4p13; 9q21-22; 12q13; 14q11; 14q32
The presence of abnormal metapahses in unstimulated
cultures was associated with failure to respond to
therapy and with shorter survival, as was the case with
+X, structural aberrations of chromosome 1, and
complex karyotype. The latter cytogenetic parameter
maintained prognostic predictivity at multivariate
analysis.
Schlegelberger B, Himmler A, Gödde E, Grote W, Feller AC,
Lennert K. Cytogenetic findings in peripheral T-cell lymphomas
as a basis for distinguishing low-grade and high-grade
lymphomas. Blood. 1994 Jan 15;83(2):505-11
Schlegelberger B, Zwingers T, Hohenadel K, Henne-Bruns D,
Schmitz N, Haferlach T, Tirier C, Bartels H, Sonnen R, Kuse R.
Significance of cytogenetic findings for the clinical outcome in
patients with T-cell lymphoma of angioimmunoblastic
lymphadenopathy type. J Clin Oncol. 1996 Feb;14(2):593-9
Cytogenetics molecular
Using probes for the detection of +3, +5 and +X, the
vast majority of cases can be shown to carry
aneuploidy.
Kumaravel TS, Tanaka K, Arif M, Ohshima K, Ohgami A,
Takeshita M, Kikuchi M, Kamada N. Clonal identification of
trisomies 3, 5 and X in angioimmunoblastic lymphadenopathy
with dysproteinemia by fluorescence in situ hybridization. Leuk
Lymphoma. 1997 Feb;24(5-6):523-32
References
Whang Peng J, Knutsen T. Cytogenetics of non Hodgkin's
lymphomas Magrath I (Ed) The non Hodgkin's lymphomas 2nd
edition. Arnold, London 1997.
Delmer A, Zittoun R. Other peripheral T-cell lymphomas.
Magrath I (Ed) The non Hodgkin's lymphomas 2nd edition..
Frizzera G, Kaneko Y, Sakurai M. Angioimmunoblastic
lymphadenopathy and related disorders: a retrospective look in
search of definitions. Leukemia. 1989 Jan;3(1):1-5
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
This article should be referenced as such:
Cuneo A, Castoldi GL. Angioimmunoblastic T-cell lymphoma.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4):286-287.
287
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
Lymphoepithelioid lymphoma
Antonio Cuneo, Gianluigi Castoldi
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/LymphoepithLymphoID2005.html
DOI: 10.4267/2042/37899
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Evolution
Identity
The disease usually runs a relatively aggressive clinical
course.
Alias
Lennert's lymphoma
Prognosis
Clinics and pathology
Median survival of 16 to 32 months was reported in
some studies.
Phenotype/cell stem origin
Cytogenetics
Peripheral CD4+ T-cell lymphoma
Epidemiology
Note
Clonal aberrations are reported in the vast majority of
cases. Chromosome 3 is frequently involved: trisomy 3;
3q rearrangements (duplication of bands 3q22-24 or
3q22 breaks) are recurrent abnormalities; A 6qchromosome was also reported.
The disease is rare.
Clinics
The patients present superficial lymph node
involvement. The cervical areas are predominantly
affected, whereas thoracic adenopathies and deep
abdominal involvement occur unfrequently at
presentation.
References
Delmer A, Zittoun R. Other peripheral T-cell lymphomas.
Magrath I (Ed) The non Hodgkin's lymphomas 2nd edition.
Pathology
The disease cannot be separated from the broad
category of peripheral T-cell lymphoma (PTL). PTL is
characterized by a heterogeneous cellular composition
with small and large cells with an inflammarory
background. Lennert's lymphoma can be recognized by
the presence of numerous epithelioid histiocytes
usually grouped in small clusters. Lennert's lymphoma
is not considered as a distinct clinicopathological
entity.
Gödde-Salz E, Feller AC, Lennert K. Cytogenetic and
immunohistochemical analysis of lymphoepithelioid cell
lymphoma (Lennert's lymphoma): further substantiation of its
T-cell nature. Leuk Res. 1986;10(3):313-23
Kristoffersson U, Heim S, Olsson H, Akerman M, Mitelman F.
Cytogenetic studies in non-Hodgkin lymphomas--results from
surgical biopsies. Hereditas. 1986;104(1):1-13
This article should be referenced as such:
Cuneo A, Castoldi GL. Lymphoepithelioid lymphoma. Atlas
Genet Cytogenet Oncol Haematol. 2002; 6(4):288.
Treatment
The disease must be treated with multiagent
chemotherapy and/or radiation therapy as for other
PTL.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
288
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Leukaemia Section
Short Communication
t(2;14)(p13;q32)
Jean Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0214p13q32ID1231.html
DOI: 10.4267/2042/37900
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
References
Disease
Ueshima Y, Bird ML, Vardiman JW, Rowley JD. A 14;19
translocation in B-cell chronic lymphocytic leukemia: a new
recurring chromosome aberration. Int J Cancer. 1985 Sep
15;36(3):287-90
Found so far in 6 cases of chronic lymphocytic
leukemia (CLL), 1 diffuse, mixed small/large cell non
Hogkin lymphoma (NHL), and 3 cases of acute
lymphocytic leukemia (ALL): one T-ALL and two
(CD10+) B-ALL.
Nishida K, Taniwaki M, Misawa S, Abe T. Nonrandom
rearrangement of chromosome 14 at band q32.33 in human
lymphoid malignancies with mature B-cell phenotype. Cancer
Res. 1989 Mar 1;49(5):1275-81
Epidemiology
Uckun FM, Gajl-Peczalska KJ, Provisor AJ, Heerema NA.
Immunophenotype-karyotype associations in human acute
lymphoblastic leukemia. Blood. 1989 Jan;73(1):271-80
Sex ratio: 5 male and 5 female patients; CLL cases
were aged 10, 15, 58, 59, and 62 years; ALL cases
were 2, 4, and 5 year old children.
Yoffe G, Howard-Peebles PN, Smith RG, Tucker PW,
Buchanan GR. Childhood chronic lymphocytic leukemia with
(2;14) translocation. J Pediatr. 1990 Jan;116(1):114-7
Prognosis
5 CLL cases were dead after 27-49 months survival;
the 3 ALL cases were alive at 29+-34+ months of
follow up.
Watson MS, Land VJ, Carroll AJ, Pullen J, Borowitz MJ, Link
MP, Amylon M, Behm FG. t(2;14)(p13;q32): a recurring
abnormality in lymphocytic leukemia. A Pediatric Oncology
Group study. Cancer Genet Cytogenet. 1992 Feb;58(2):121-4
Cytogenetics
Geisler CH, Philip P, Christensen BE, Hou-Jensen K,
Pedersen NT, Jensen OM, Thorling K, Andersen E, Birgens
HS, Drivsholm A, Ellegaard J, Larsen JK, Plesner T, Brown P,
Andersen PK, Hansen MM. In B-cell chronic lymphocytic
leukaemia chromosome 17 abnormalities and not trisomy 12
are the single most important cytogenetic abnormalities for the
prognosis: a cytogenetic and immunophenotypic study of 480
unselected newly diagnosed patients. Leuk Res. 1997 NovDec;21(11-12):1011-23
Cytogenetics morphological
Sole anomaly in 2 of 8 documented cases; often found
in complex karyotypes; no recurrent accompanying
anomaly so far.
Genes involved and proteins
Sonoki T, Matsuzaki H, Satterwhite E, Nakazawa N, Hata H,
Tucker PW, Taniwaki M, Kuribayashi N, Harada N, Matsuno F,
Mitsuya H. A plasma cell leukemia patient showing bialleic 14q
translocations: t(2;14) and t(11;14). Acta Haematol.
1999;101(4):197-201
BCL11A
Location
2p13-15
Protein
6 Kruppel C2H2 zinc fingers, a prolin rich domain, and
an acidic domain.
Satterwhite E, Sonoki T, Willis TG, Harder L, Nowak R, Arriola
EL, Liu H, Price HP, Gesk S, Steinemann D, Schlegelberger B,
Oscier DG, Siebert R, Tucker PW, Dyer MJ. The BCL11 gene
family: involvement of BCL11A in lymphoid malignancies.
Blood. 2001 Dec 1;98(12):3413-20
IgH
This article should be referenced as such:
Location
14q32
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Huret JL. t(2;14)(p13;q32). Atlas Genet Cytogenet Oncol
Haematol. 2002; 6(4):289.
289
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(5;14)(q35;q32)
Roland Berger
Inserm U 434 and SD 401 No. 434 CNRS, Institut de Génétique Moléculaire, 27, rue Juliette Dodu, 75010
Paris, France (RB)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0514q35q32ID1227.html
DOI: 10.4267/2042/37901
This article is an update of: Huret JL. t(5;14)(q35;q32). Atlas Genet Cytogenet Oncol Haematol.2002;6(2):130-131.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
t(5;14)(q35;q32) FISH - Courtesy Melanie Zenger and Claudia Haferlach.
Clinics and pathology
Prognosis
Disease
Present data suggest that t(5;14)(q35;q32) is associated
with poor outcome, but confirmatory data is necessary
prior to conclude.
T cell acute lymphoblastic leukemia (ALL).
Phenotype/cell stem origin
Cytogenetics
Cortical T cell leukemia (CD1a+, CD10+).
Cytogenetics morphological
Epidemiology
Cryptic translocation (banded karyotype). Often
apparently normal karyotype with banding techniques.
Frequent in T-cell ALL in children (in about 20% of
childhood T-cell ALLs); less frequent in adult T-ALL.
Not seen in B-cell ALL.
Cytogenetics molecular
t(5;14)(q35;q32) can be detected with FISH techniques.
Several probes may be used: chromosome painting,
combination of painting probes and YAC, multicolor-
Cytology
FAB nomenclature: L1 or L2 ALL.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
290
t(5;14)(q35;q32)
Berger R
FISH with adequate probes. The localization of the
chromosomal breakpoint with BACs/PACs will be
performed in a second step.
Result of the chromosomal
anomaly
Additional anomalies
Fusion protein
Variable.
Description
No fusion protein, but abnormal expression of
HOX11L2.
Oncogenesis
HOX11L2 is transcriptionally activated, due to control
by CITP2 regulatory sequences.
Genes involved and proteins
Note
The consequence of the translocation is the ectopic
expression of the HOX11L2, gene normally located to
5q35, and normally not expressed in ALL without 5q
rearrangement. The "deregulation" of HOX11L2
expression is thought to result from abnormal control of
the gene by CTPI2, located to 14q32, as a consequence
of the chromosomal rearrangement. The chromosome 5
breakpoint is usually located within the locus of
another gene, RanBP17, often disrupted by the
chromosomal rearrangement. The breakpoint on
chromosome 5 is consequently distant from the gene
abnormally expressed (HOX11L2).
References
Bernard OA, Busson-LeConiat M, Ballerini P, Mauchauffé M,
Della Valle V, Monni R, Nguyen Khac F, Mercher T, PenardLacronique V, Pasturaud P, Gressin L, Heilig R, Daniel MT,
Lessard M, Berger R. A new recurrent and specific cryptic
translocation, t(5;14)(q35;q32), is associated with expression
of the Hox11L2 gene in T acute lymphoblastic leukemia.
Leukemia. 2001 Oct;15(10):1495-504
Ballerini P, Blaise A, Busson-Le Coniat M, Su XY, ZucmanRossi J, Adam M, van den Akker J, Perot C, Pellegrino B,
Landman-Parker J, Douay L, Berger R, Bernard OA. HOX11L2
expression defines a clinical subtype of pediatric T-ALL
associated with poor prognosis. Blood. 2002 Aug 1;100(3):9917
HOX11L2
Location
5q35
Protein
Homeobox domain; belongs to HOX 11 family.
Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C,
Raimondi SC, Behm FG, Pui CH, Downing JR, Gilliland DG,
Lander ES, Golub TR, Look AT. Gene expression signatures
define novel oncogenic pathways in T cell acute lymphoblastic
leukemia. Cancer Cell. 2002 Feb;1(1):75-87
Hélias C, Leymarie V, Entz-Werle N, Falkenrodt A, Eyer D,
Costa JA, Cherif D, Lutz P, Lessard M. Translocation
t(5;14)(q35;q32) in three cases of childhood T cell acute
lymphoblastic leukemia: a new recurring and cryptic
abnormality. Leukemia. 2002 Jan;16(1):7-12
This article should be referenced as such:
Berger R. t(5;14)(q35;q32). Atlas Genet Cytogenet Oncol
Haematol. 2002; 6(4):290-291.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
291
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in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
Acute Erythroid leukaemias
Sally Killick, Estella Matutes
Department of Haematology, St George's Hospital Medical School, London, UK (EM)
Published in Atlas Database: July 2002
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/M6ANLLID1215.html
DOI: 10.4267/2042/37902
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
chromatin, distinct nucleoli and deeply basophilic
cytoplasm that often have vacuoles. Occasionally the
blasts can resemble acute lymphoblastic leukaemia,
distinction can be made by immunophenotyping. The
erythroid nature of the blasts can be shown by electron
microscopy demonstrating free ferritin particles. The
blasts are negative for Sudan black B and
myeloperoxidase (MPO), but positive for PAS in a
block pattern.
Identity
Alias
M6-ANLL erythroleukaemia and pure erythoid
leukaemia.
Note
Criteria for diagnosis of acute erythroid leukaemia.
Erythroleukaemia
Historically, AML with erythroid features has been
designated M6 by the French-American-British (FAB)
group. The FAB criteria for M6 diagnosis are: bone
marrow erythroblasts equal to or greater than 50% and
blasts equal to or greater than 30% of the non-erythroid
cells. The World Health Organization (WHO) have
recently recommended that the requisite blast
percentage for a diagnosis of AML be 20% or greater,
and this includes erythroid leukaemia. AML M6 would
equate to the new WHO definition of erythroleukaemia
(erythroid/ myeloid). If there are less than 20% blasts,
the diagnosis is refractory anaemia with an excess of
blasts (RAEB). Trilineage dysplasia is common but is
not a prerequisite for diagnosis. Erythroid dysplasia
may manifest as binuclearity, nucleo-cytoplasmic
asynchrony and vacuolation. The morphological
appearance of the myeloblasts is not characteristic and
they may contain Auer rods. Myeloperoxidase and
Sudan black B stains may be positive in the
myeloblasts. The iron stain may show ringed
sideroblasts and PAS may be positive in the erythroid
precursors in a block or diffuse pattern.
Pure erythoid leukaemia
In addition to the typical AML M6 (erythroleukaemia), there is a second subtype of acute erythoid
leukaemia where there is a neoplastic proliferation of
immature cells entirely committed to the erythroid
series (>80% of marrow cells) without evidence of a
myeloid component. This is termed pure erythroid
leukaemia by the WHO. Morphology is characterised
by medium sized erythroblasts with fine nuclear
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Clinics and pathology
Epidemiology
Acute erythroid leukaemia is an uncommon form of
acute myeloid leukaemia (AML), accounting for
approximately 3-4% of cases. Perhaps more than other
subtypes of AML, it may represent the evolution or
transformation of a myelodysplastic syndrome (MDS),
and may be secondary to previous chemotherapy,
immunosuppressive treatment or radiotherapy given for
a wide range of malignant or non-malignant diseases. It
is more commonly associated with exposure to
alkylating agents or benzene than other subtypes of
AML.
Clinics
Acute erythroid leukaemia presents with symptoms and
signs of cytopenias. It is more common in adults than
in children.
Cytology
Immunophenotype
- Erythroleukaemia: The myeloid blasts express a
variety of myeloid markers, similar to othe subtypes of
AML - CD13, CD33, CD117 (ckit) and MPO. The
erythroblasts lack myeloid antigens but are positive to
glycophorin A.
- Pure erythroid leukaemia: Erythroid blasts which
have differentiated will be positive with glycophorin A
but negative with MPO and myeloid markers. The
292
Acute Erythroid leukaemias
Killick S, Matutes E
more immature blasts are difficult to identify as
erythroid because they are usually negative for
glycophorin A. Immature erythroid progenitors may be
detected using carbonic anhydrase 1 or CD36.
Although CD36 is not specific for erythroid
progenitors, negative markers for megakaryocytes and
monocytes will aid the diagnosis.
References
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA,
Gralnick HR, Sultan C. Proposed revised criteria for the
classification of acute myeloid leukemia. A report of the
French-American-British Cooperative Group. Ann Intern Med.
1985 Oct;103(4):620-5
Breton-Gorius J, Villeval JL, Mitjavila MT, Vinci G, Guichard J,
Rochant H, Flandrin G, Vainchenker W. Ultrastructural and
cytochemical characterization
of
blasts
from
early
erythroblastic leukemias. Leukemia. 1987 Mar;1(3):173-81
Treatment
The prognosis of acute erythroid leukaemia is reported
as poor. It is, however, important to differentiate de
novo from secondary or therapy related erythroid
leukaemia, where the later have a worse prognosis.
Remission induction for de novo disease is similar to
other subtypes of AML; however the poor outcome has
been linked to short remission duration. Patients with
complex karyotypes or abnormalities of chromosomes
5 and/or 7 have a higher relapse rate than those with
normal or simple karyotypes. Data from the Medical
Research Council AML10 trial show reduced relapse
rates in patients with both standard and poor risk AML
after autologous bone marrow transplantation. It may,
therefore, be reasonable to consider early stem cell
transplantation in first complete remission in patients
with acute erythroid leukaemia, particularly those with
a poor risk karyotype.
Cuneo A, Van Orshoven A, Michaux JL, Boogaerts M,
Louwagie A, Doyen C, Dal Cin P, Fagioli F, Castoldi G, Van
den Berghe H. Morphologic, immunologic and cytogenetic
studies in erythroleukaemia: evidence for multilineage
involvement and identification of two distinct cytogeneticclinicopathological types. Br J Haematol. 1990 Jul;75(3):34654
Olopade OI, Thangavelu M, Larson RA, Mick R, Kowal-Vern A,
Schumacher HR, Le Beau MM, Vardiman JW, Rowley JD.
Clinical, morphologic, and cytogenetic characteristics of 26
patients with acute erythroblastic leukemia. Blood. 1992 Dec
1;80(11):2873-82
Burnett AK, Goldstone AH, Stevens RM, Hann IM, Rees JK,
Gray RG, Wheatley K. Randomised comparison of addition of
autologous bone-marrow transplantation to intensive
chemotherapy for acute myeloid leukaemia in first remission:
results of MRC AML 10 trial. UK Medical Research Council
Adult and Children's Leukaemia Working Parties. Lancet. 1998
Mar 7;351(9104):700-8
Cytogenetics
Killick S, Matutes E, Powles RL, Min T, Treleaven JG, Rege
KP, Atra A, Catovsky D. Acute erythroid leukemia (M6):
outcome of bone marrow transplantation. Leuk Lymphoma.
1999 Sep;35(1-2):99-107
Cytogenetics morphological
There is no unique chromosome abnormality described
in acute erythroid leukaemia, however complex
karyotypes with multiple structural abnormalities are
common. Chromosomes 5 and 7 are the most
frequently affected. These findings are also
characteristically found in therapy-related AML and
MDS, however loss or deletion of 5q is higher in de
novo erythroid leukaemia whilst loss or deletion of 7q
is higher in therapy related AML.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Jaffe EE, Harris NL, Stein H, Vardiman J. WHO Tumours of
haemopoietic and lymphoid tissues. IRAC Press, 2001.
This article should be referenced as such:
Killick S, Matutes E. Acute Erythroid leukaemias. Atlas Genet
Cytogenet Oncol Haematol. 2002; 6(4):292-293.
293
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(1;13)(q32;q14)
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: July 2002
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0113q32q14ID1251.html
DOI: 10.4267/2042/37904
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
t(1;13)(q32;q13) G- banding - Courtesy Melanie Zenger and Claudia Haferlach.
Clinics and pathology
Prognosis
Disease
One patient died at 10 mths, the other is alive at 24
months+.
Diffuse large B-cell lymphoma (DLBCL).
Cytogenetics
Epidemiology
Cytogenetics morphological
Only 2 cases so far, aged 39 and 57 years; 2 male
patients.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Unbalanced form der(1)t(1;13) in one case.
294
t(1;13)(q32;q14)
Huret JL
Cytogenetics molecular
References
The anomaly had been uncovered by SKY.
Nanjangud G, Rao PH, Hegde A, Teruya-Feldstein J, Donnelly
G, Qin J, Jhanwar SC, Zelenetz AD, Chaganti RS. Spectral
karyotyping identifies new rearrangements, translocations, and
clinical associations in diffuse large B-cell lymphoma. Blood.
2002 Apr 1;99(7):2554-61
Genes involved and proteins
Note
Genes involved are yet unknown.
This article should be referenced as such:
Huret JL. t(1;13)(q32;q14). Atlas Genet Cytogenet Oncol
Haematol. 2002; 6(4):294-295.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
295
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(1;7)(q21;q22)
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: July 2002
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0107q21q22ID1252.html
DOI: 10.4267/2042/37903
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Cytogenetics molecular
Clinics and pathology
The anomaly had been uncovered by SKY.
Disease
Genes involved and proteins
Diffuse large B-cell lymphoma (DLBCL).
Epidemiology
Note
Genes involved are yet unknown.
Only 2 cases so far, aged 43 and 66 years; 1 male and 1
female patient.
References
Pathology
Nanjangud G, Rao PH, Hegde A, Teruya-Feldstein J, Donnelly
G, Qin J, Jhanwar SC, Zelenetz AD, Chaganti RS. Spectral
karyotyping identifies new rearrangements, translocations, and
clinical associations in diffuse large B-cell lymphoma. Blood.
2002 Apr 1;99(7):2554-61
The 2 cases were centroblastic.
Prognosis
Patients died at 10 months and 33 mths.
Cytogenetics
This article should be referenced as such:
Cytogenetics morphological
Huret JL. t(1;7)(q21;q22). Atlas Genet Cytogenet Oncol
Haematol. 2002; 6(4):296.
Unbalanced form der(1)t(1;7) in one case.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
296
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(3;14)(q21;q32)
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: July 2002
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0314q21q32ID1250.html
DOI: 10.4267/2042/37905
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Cytogenetics molecular
Clinics and pathology
The anomaly had been uncovered by SKY.
Disease
References
Diffuse large B-cell lymphoma (DLBCL).
Epidemiology
Nanjangud G, Rao PH, Hegde A, Teruya-Feldstein J, Donnelly
G, Qin J, Jhanwar SC, Zelenetz AD, Chaganti RS. Spectral
karyotyping identifies new rearrangements, translocations, and
clinical associations in diffuse large B-cell lymphoma. Blood.
2002 Apr 1;99(7):2554-61
Only 2 cases so far, aged 73 and 83 years, 1 male and 1
female patients.
Prognosis
5 mths+ and lost to follow up.
This article should be referenced as such:
Cytogenetics
Huret JL. t(3;14)(q21;q32). Atlas Genet Cytogenet Oncol
Haematol. 2002; 6(4):297.
Cytogenetics morphological
Unbalanced form der(14) t(3;14) in 1 case, three way
translocation t(1;3.14) in the other case.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
297
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(4;11)(q21;p15)
Franck Viguié
Laboratoire de Cytogénétique - Service d'Hématologie Biologique, Hôpital Hôtel-Dieu, 75181 Paris Cedex
04, France (FV)
Published in Atlas Database: July 2002
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0411q21p15ID1191.html
DOI: 10.4267/2042/37906
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics
Identity
No notable particular aspect.
Note
Not to be confused with a variant of the classical t(4
;11)(q21;q23) translocation.
Prognosis
Probably unfavorable, median survival below 18
months; improved by allogeneic bone marrow
transplantation.
Cytogenetics
Cytogenetics morphological
In approximately 2/3 of cases; 2 cases with 12p-.
Cytogenetics molecular
Two BAC clones 290A12 and 118H17 (California
Institute of Technology BAC library) encompasses all
NUP98 gene and are split by translocation.
Variants
Not described.
Genes involved and proteins
t(4;11)(q21;p15) G- banding - Courtesy Diane H. Norback, Eric
B. Johnson, Sara Morrison-Delap Cytogenetics at theWaisman
Center
RAP1GDS1
Clinics and pathology
Location
4q22.3
Protein
SmgGDS, 558 amino acids; stimulates GDP --> GTP
transition in a series of small GTP-binding proteins (g
proteins) including rap1a, rap1b, K-ras, rac1, rac2,
rhoA and ralB.
Somatic mutations
Not involved in other known clonal rearrangement
associated with tumoral proliferation.
Disease
T-cell acute lymphoblastic leukemia.
Phenotype/cell stem origin
Lymphoblasts, either L1 or L2 in the FAB
classification; mature T and myeloid markers variably
co-expressed.
Epidemiology
Rare, approximately 10 cases described; evaluated to 25% of adult T-ALL; not evaluated in childhood ALL;
both sexes equally involved; found in children or young
adults.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
NUP98
Location
11p15.4
298
t(4;11)(q21;p15)
Viguié F
t(4;11) generates only one chimeric protein 5' - NUP98
- RAP1GDS1 - 3' which contains a variable part of
NUP98 and the totality of smgGDS except for the
initial methionine.
Protein
Nucleoporin 98, a 98 kDa component of the nuclear
pore complex implicated in nucleo-cytoplasmic
transport.
Somatic mutations
involved in different types of acute myeloid leukemia,
as fusion gene with HOX A9, DDX10, HOX D13,
TOP1, PMX1 and LEDGF, resulting respectively from
t(7;11)(p15;p15), inv(11)(p15q22), t(2;11)(q31;p15),
t(11;20)(p15;q11),
t(1;11)(q23;p15)
and
t(9;11)(p22;p15).
References
Kalatzis V, Peters GB, Dobrovic A. Mapping of the
chromosome 11 breakpoint of the t(4;11)(q21;p14-15)
translocation. Cancer Genet Cytogenet. 1993 Sep;69(2):122-5
Hussey DJ, Nicola M, Moore S, Peters GB, Dobrovic A. The
(4;11)(q21;p15) translocation fuses the NUP98 and
RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic
leukemia. Blood. 1999 Sep 15;94(6):2072-9
Result of the chromosomal
anomaly
Mecucci C, La Starza R, Negrini M, Sabbioni S, Crescenzi B,
Leoni P, Di Raimondo F, Krampera M, Cimino G, Tafuri A,
Cuneo A, Vitale A, Foà R. t(4;11)(q21;p15) translocation
involving NUP98 and RAP1GDS1 genes: characterization of a
new subset of T acute lymphoblastic leukaemia. Br J
Haematol. 2000 Jun;109(4):788-93
Hybrid gene
Description
NUP98 breakpoint in the intron between exons B and
C; 5'-part of NUP98 is fused in frame with the whole
coding sequence of RAP1GDS1; fusion gene called
NRG: 5'-NUP-RAP1GDS1-3'. Variant described with
breakpoint in NUP98 before exon A.
Cimino G, Sprovieri T, Rapanotti MC, Foà R, Mecucci C,
Mandelli F. Molecular evaluation of the NUP98/RAP1GDS1
gene frequency in adults with T-acute lymphoblastic leukemia.
Haematologica. 2001 Apr;86(4):436-7
This article should be referenced as such:
Fusion protein
Viguié F. t(4;11)(q21;p15). Atlas Genet Cytogenet Oncol
Haematol. 2002; 6(4):298-299.
Description
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
299
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(6;8)(q11;q11)
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: July 2002
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0608q11q11ID1253.html
DOI: 10.4267/2042/37907
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Genes involved and proteins
Disease
Diffuse large B-cell lymphoma (DLBCL).
Note
Genes involved are yet unknown.
Epidemiology
References
Only 2 cases so far, aaged 42 and 57 years; 2 female
patients.
Nanjangud G, Rao PH, Hegde A, Teruya-Feldstein J, Donnelly
G, Qin J, Jhanwar SC, Zelenetz AD, Chaganti RS. Spectral
karyotyping identifies new rearrangements, translocations, and
clinical associations in diffuse large B-cell lymphoma. Blood.
2002 Apr 1;99(7):2554-61
Prognosis
One patient is alive at 12 months+, the other one died at
31 mths.
This article should be referenced as such:
Cytogenetics
Huret JL. t(6;8)(q11;q11). Atlas Genet Cytogenet Oncol
Haematol. 2002; 6(4):300.
Cytogenetics morphological
The anomaly had been uncovered by SKY.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
300
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Mini Review
Head and neck squamous cell carcinoma
Hélène Blons
U490 INSERM Toxicologie Moléculaire, 45 rue des saints pères, 75006 Paris, France (HB)
Published in Atlas Database: May 2002
Online updated version: http://AtlasGeneticsOncology.org/Tumors/HeadNeckSquamID6368.html
DOI: 10.4267/2042/37908
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
in DNA repair enzymes or in carcinogens metabolizing
enzymes supports the role of heredity in HNSCC.
Among the polymorphism tested, GSTM1 and GSTT1
null phenotypes are associated with an increased risk of
HNSCC. Concerning XRCC1, the Arg allele
(Arg194Trp) and the Gln allele (Arg399Gln) are also
linked to an increased risk of oral and pharyngeal
cancers.
Clinics and pathology
Disease
Head and neck cancer as defined here includes the
squamous cell carcinomas of the oral cavity, pharynx
and larynx. This malignancy is an important public
health problem worldwide with more than 500000 new
cases diagnosed each year. Patients often present with
advanced stage disease and despite combined therapy
outcome remains poor. For early stage, patients can be
at high risk for second primary when cured of their
initial cancer which poses the main threat to survival.
Pathology
Head and neck cancer are usually diagnosed in men
after 50, patients can present with one or more distinct
localization (10-15% at diagnosis) and 25% will
develop a second cancer within 5 years from diagnosis.
Cancer can develop from leucoplakia, erythroplakia or
apparently normal epithelium. Premalignant lesions
showing abnormal DNA content are at high risk of
transformation. Clinical prognosis factors counts,
tumor size, node involvement and smoking habits.
Tumor markers related to prognosis counts EGFR
expression, cyclin D1 or cyclin E expression, serum
soluble IL-2 receptor concentrations and loss of
chromosome arm 18q.
Etiology
The major risk factor for head and neck cancer is
chronic exposure of epithelia to tobacco smoke and
alcohol. Environmental factors such as wood and
cement dusts as well as human papilloma virus type 16
and 18 (HPV) infection have been related to an
increased risk of developing head and neck squamous
cell carcinoma (HNSCC). Recent studies confirm that
oropharyngeal tumors are often HPV-positive and
compose a distinct clinical and pathological entity with
less TP53 mutations and better prognosis as compared
to HPV negative tumors. Epstein Barr Virus infection
is related to nasopharyngeal SCC in south china and
oral cavity tumors are frequent in betel chewers.
Treatment
First goal is locoregional control achieved by surgery
or radiotherapy. For high staged tumors combined
surgery+/-radiotherapy+/-chemotherapy can be used.
New treatment strategies are in development.
Adenovirus have been developed that restore TP53 or
P16 activity or that selectively replicates in TP53
deficient cells. Agents that inhibit signal transduction
as tyrosine kinase inhibitors are also under evaluation
in HNSCC specially those targeting the EGF receptor.
Epidemiology
Both hereditary and environmental factors are
implicated in head and neck carcinogenesis and their
roles are difficult to separate. Several cancer prone
syndromes are associated with a increased risk of head
and neck cancer, including Lynch-II, Bloom syndrome,
Fanconi anemia, ataxia telagiectasia and Li-fraumeni
syndrome. But genetic susceptibility to head and neck
cancer is more likely to be due to various degrees of
DNA maintenance after exposure to tobacco
carcinogens. Mutagen sensitivity tests, polymorphism
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Cytogenetics
Note
Chromosomal abnormalities are very frequent in head
and neck tumors leading to very complex caryotypes
301
Head and neck squamous cell carcinoma
Blons H
- Chromosome arm 13q: No mutation in RB were
identified in HNSCC.
- Chromosome arm 10q: No mutation in PTEN were
identified in HNSCC.
Oncogenes
- Chromosome band 11q13: EMS1, FGF3, FGF4 et
CCND1 are amplified in HNSCC.
- Chromosome arm 3q: The PIK3CA gene but not p63
is likely to be the target of 3q26-qter gain.
- The Wnt, APC, bcatenin pathway: No mutation in the
bcatenin gene in HNSCC.
- MAP kinase pathway: The only head and neck tumors
with constitutive RAS activation are from Indian and
Taiwanese patients that can harbor HRAS or KRAS
mutation.
- Epigenetic alteration in HNSCC: Genes can be
inactivated by promoter hypermethylation, in head and
neck cancer the phenomenon has been demonstrated
for several genes including P16, MGMT and DAPkinase. DAP-kinase is implicated in INFg mediated
apoptosis and DAP-kinase promoter hypermethylation
is related to advance stage tumors.
with more than 70% of tumors being aneuploïd.
Although most chromosome arms can be targeted by
loss or gain of fragments, cytogenetic studies,
Comparative Genome Hybridization (CGH) studies and
molecular genetics studies demonstrated the existence
of recurrent alterations some of which are found early
in carcinogenesis. Loss of chromosome arm 3p and/or
9p is found in over 80% of tumors, loss of 17p involves
more than 50% of the cases these alterations are
associated with early tumor development. Losses of 5q,
8p, 4q 10q or 13q are found in nearly 30% of tumors
and loss of 11p in less than 20% these alterations are
preferentially associated with tumor progression.
Concerning fragments gain, amplification at 11q and 3q
clearly participate in head and neck carcinogenesis and
concern nearly 70% of the cases. 3q amplification is
seen in early tumor development. Studies showed that
patterns of chromosomal alterations can be associated
with clinical parameters such as deletions at 10q25-q26
and 11p13-p14 that are significant for metastasizing
carcinoma and amplification of 11q could be a bad
prognosis factor.
Tumor proliferation is known to result from activation
of growth promoting pathways and inhibition of growth
downregulation pathways. Several chromosomal
segments involved in head and neck carcinogenesis
harbor genes implicated in growth regulation.
Tumor suppressor genes
- Chromosome arm 3p: At least three regions have been
identified at 3p 3p13-3p21, 3p21.3-3p23, 3p25. Four
genes have been studied for the presence of inactivating
mutations VHL, TGFbRII, FHIT and OGG1. Very few
mutations have been found in TGFbRII and only
abnormal transcripts were detected for FHIT leading to
the conclusion that it is still unclear whether or not
these genes are the targets of 3p deletions.
- Chromosome arm 9p: CDNK2A (P16) is a cell cycle
regulatory gene located at 9p that is down regulated in
HNSCC through homozygous deletion or promoter
hypermethylation.
- Chromosome arm 17p: TP53 is mutated in over 60%
of HNSCC there is a good correlation between
mutation and LOH at 17p. In HNSCC 50% of TP53
mutations are nonsense, deletions, insertions or splice
site junctions mutations and 50% are missenses. It has
been clearly demonstrated that smoke carcinogens have
a causal role in the formation of TP53 mutations and
that the prevalence is greater in heavy smoker patients.
TP53 mutations could be an indicator of a bad response
to neoadjuvant chemotherapy in HNSCC
- Chromosome arm 18q: Loss of 18q is linked to bad
prognosis in HNSCC. Genes SMAD2, SMAD4 and
DCC do not seem to be the right targets. The
delineation of a common region of loss at 18q22 did
not allow the identification of a new tumor suppressor
gene.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
References
Decker J, Goldstein JC. Risk factors in head and neck cancer.
N Engl J Med. 1982 May 13;306(19):1151-5
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Mao L, Fan YH, Lotan R, Hong WK. Frequent abnormalities of
FHIT, a candidate tumor suppressor gene, in head and neck
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Waziers I, Hamelin R, Brasnu D, Beaune P, Laurent-Puig P.
Microsatellite analysis and response to chemotherapy in headand-neck squamous-cell carcinoma. Int J Cancer. 1999 Aug
20;84(4):410-5
Mao L, Lee JS, Fan YH, Ro JY, Batsakis JG, Lippman S,
Hittelman W, Hong WK. Frequent microsatellite alterations at
chromosomes 9p21 and 3p14 in oral premalignant lesions and
their value in cancer risk assessment. Nat Med. 1996
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Glutathione-S-transferase polymorphisms and risk of
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1999 Jun 21;84(3):220-4
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KD. Amplification and expression of EMS-1 (cortactin) in head
and neck squamous cell carcinoma cell lines. Oncogene. 1996
Jan 4;12(1):31-5
Gupta VK, Schmidt AP, Pashia ME, Sunwoo JB, Scholnick SB.
Multiple regions of deletion on chromosome arm 13q in headand-neck squamous-cell carcinoma. Int J Cancer. 1999 Oct
22;84(5):453-7
El-Naggar AK, Lai S, Clayman G, Lee JK, Luna MA, Goepfert
H, Batsakis JG. Methylation, a major mechanism of
p16/CDKN2 gene inactivation in head and neck squamous
carcinoma. Am J Pathol. 1997 Dec;151(6):1767-74
Sturgis EM, Castillo EJ, Li L, Zheng R, Eicher SA, Clayman
GL, Strom SS, Spitz MR, Wei Q. Polymorphisms of DNA repair
gene XRCC1 in squamous cell carcinoma of the head and
neck. Carcinogenesis. 1999 Nov;20(11):2125-9
Frank CJ, McClatchey KD, Devaney KO, Carey TE. Evidence
that loss of chromosome 18q is associated with tumor
progression. Cancer Res. 1997 Mar 1;57(5):824-7
Bartsch H, Nair U, Risch A, Rojas M, Wikman H, Alexandrov K.
Genetic polymorphism of CYP genes, alone or in combination,
as a risk modifier of tobacco-related cancers. Cancer
Epidemiol Biomarkers Prev. 2000 Jan;9(1):3-28
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Dietel M, Petersen I. Genomic alterations associated with
malignancy in head and neck cancer. Head Neck. 1998
Mar;20(2):145-51
Cabelguenne A, Blons H, de Waziers I, Carnot F, Houllier AM,
Soussi T, Brasnu D, Beaune P, Laccourreye O, Laurent-Puig
P. p53 alterations predict tumor response to neoadjuvant
chemotherapy in head and neck squamous cell carcinoma: a
prospective series. J Clin Oncol. 2000 Apr;18(7):1465-73
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Ro JY, El-Naggar A, Hong WK, Hittelman WN. Dysregulated
cyclin D1 expression early in head and neck tumorigenesis: in
vivo evidence for an association with subsequent gene
amplification. Oncogene. 1998 Nov 5;17(18):2313-22
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J, Hörmann K. Fhit expression is absent or reduced in a subset
of primary head and neck cancer. Anticancer Res. 2000 MarApr;20(2A):1057-60
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Halachmi N, Ahrendt SA, Reed AL, Hilgers W, Kern SE, Koch
WM, Sidransky D, Jen J. Analysis of PTEN/MMAC1 alterations
in aerodigestive tract tumors. Cancer Res. 1998 Feb
1;58(3):509-11
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Lorenz G. First hints for a correlation between amplification of
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and neck squamous cell carcinomas. J Oral Pathol Med. 2000
Oct;29(9):432-7
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Rybicki BA, Dyke DL. Loss of 18q predicts poor survival of
patients with squamous cell carcinoma of the head and neck.
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Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck
cancer. N Engl J Med. 2001 Dec 27;345(26):1890-900
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Mutagen sensitivity to benzo(a)pyrene diol epoxide and the risk
of squamous cell carcinoma of the head and neck. Clin Cancer
Res. 1998 Jul;4(7):1773-8
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
This article should be referenced as such:
Blons H. Head and neck squamous cell carcinoma. Atlas
Genet Cytogenet Oncol Haematol. 2002; 6(4):301-303.
303
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in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Congenital neutropenia
Jay L Hess
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 413b
Stellar Chance Laboratories, Philadelphia, PA 19104, USA (JLH)
Published in Atlas Database: May 2002
Online updated version: http://AtlasGeneticsOncology.org/Kprones/CongenitNeutropID10073.html
DOI: 10.4267/2042/37909
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
common in males. Cyclic forms are slightly more
common in females.SCN patients develop frequent
fevers, skin infections and stomatitis with organisms
such as E. coli, S. aureus, and Pseudomonas species.
90% of patients are diagnosed by 6 months of age.
Patients tend to develop hematological malignancies
(see below).
Pathology: The absolute neutrophil count is usually
less than 0.2x109 /L. The bone marrow of affected
patients shows an arrest in maturation at the
promyelocyte stage, often with a monocytosis and
sometimes with eosinophilia. The peripheral blood
shows a paucity of neutrophils and often monocytosis
and eosinophilia.
Identity
Alias
Severe chronic neutropenia (SCN)
Kostmann syndrome
Note
Severe chronic neutropenia is a general term that
applies to both congenital and acquired cases.
Kostmann syndrome is a subtype of chronic
neutropenia with onset in early childhood with an
autosomal recessive pattern of development. The term
congenital neutropenia is used interchangeably
although some authors argue that the term is more
appropriate for sporadic cases.
Neoplastic risk
Clinics
Roughly 50% of patients present with myelodysplastic
syndromes (MDS), another 10% with therapy
associated MDS, 25% with de novo acute myeloid
leukemia (AML), and the remainder with a range of
other myeloproliferative disorders. The majority of
MDS patients transform into AML with a short
preleukemic phase.
Note
Severe chronic neutropenia (SCN) is a heterogeneous
group of disorders characterized by chronic neutropenia
and serious recurrent infections. The defining
characteristic of all of these diseases is the presence of
severe neutropenia with absolute neutrophil counts of
less than 0.5x109 /L on three separate occasions over a
six week period. Some clinically distinctive cases,
known as cyclic neutropenia show oscillation in
neutrophil levels with a periodicity of approximately 21
days. SCN is distinguished from ShwatchmanDiamond Syndrome by the absence of exocrine
pancreas deficiency and growth retardation.
Treatment
More than 90% of patients respond to G-CSF therapy,
which may result in cyclic oscillations in neutrophil
count. G-CSF therapy may be complicated by
significant bone loss and the development of AML.
Hematopoietic stem cell transplantation has shown
promise in the treatment of non-responders.
Phenotype and clinics
Prognosis
Phenotype stem cell origin: Constitutional disorder
affecting myeloid lineage cells.
Epidemiology: The disease is most common in
causcasians and presents in childhood.
Clinical features: Congenital neutropenia usually
presents in early childhood and is slightly more
With the advent of G-CSF therapy infectious deaths are
rare. Approximately 10% of patients develop AML.
This is associated in almost all cases with G-CSF-R
mutations. This is not thought to be the direct result of
G-CSF therapy but rather an underlying predisposition
for the development of myeloid leukemia. Cyclic
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
304
Congenital neutropenia
Hess JL
Belaaouaj A, McCarthy R, Baumann M, Gao Z, Ley TJ,
Abraham SN, Shapiro SD. Mice lacking neutrophil elastase
reveal impaired host defense against gram negative bacterial
sepsis. Nat Med. 1998 May;4(5):615-8
neutropenia patients do not have an increased risk for
development of acute leukemia.
Cytogenetics
Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC.
Mutations in ELA2, encoding neutrophil elastase, define a 21day biological clock in cyclic haematopoiesis. Nat Genet. 1999
Dec;23(4):433-6
Inborn conditions
The majority of patients have point mutations involving
neutrophil elastase located at chromosome 19p13.3.
Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla
MA, Boxer LA, Kannourakis G, Zeidler C, Welte K, Benson KF,
Horwitz M. Mutations in the gene encoding neutrophil elastase
in congenital and cyclic neutropenia. Blood. 2000 Oct
1;96(7):2317-22
Cytogenetics of cancer
Cases complicated by the development of AML most
commonly show monosomy 7or trisomy 21. Activating
RAS mutations are seen in roughly 50% of secondary
AML cases.
Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla
MA, Boxer LA, Kannourakis G, Zeidler C, Welte K, Benson KF,
Horwitz M. Mutations in the gene encoding neutrophil elastase
in congenital and cyclic neutropenia. Blood. 2000 Oct
1;96(7):2317-22
Genes involved and proteins
Freedman MH, Bonilla MA, Fier C, Bolyard AA, Scarlata D,
Boxer LA, Brown S, Cham B, Kannourakis G, Kinsey SE, Mori
PG, Cottle T, Welte K, Dale DC. Myelodysplasia syndrome and
acute myeloid leukemia in patients with congenital neutropenia
receiving G-CSF therapy. Blood. 2000 Jul 15;96(2):429-36
Note
Most patients show point mutations in ELA2, a protein
that is present in azurophilic granules. In one series of
22 patients 17 different mutations were identified. Most
of these were missense mutations. The association
between defects in the serine protease ELA2 and
neutropenia is thought to involve shortened myeloid
progenitor survival. The mechanism of this is obscure.
This does not appear to be either loss of function or
gain of function (i.e. through cytotoxicity). The
evidence to date best supports a dominant negative
mechanism whereby the activity of the wild type
protein is inhibited. One report suggested that mutation
of ELA2 alone was not sufficient for the neutropenia
phenotype. It is noteworthy in this regard that mice
with knockout of ELA2 show disorders in neutrophil
function but not neutropenia.
Zeidler C, Welte K, Barak Y, Barriga F, Bolyard AA, Boxer L,
Cornu G, Cowan MJ, Dale DC, Flood T, Freedman M, Gadner
H, Mandel H, O'Reilly RJ, Ramenghi U, Reiter A, Skinner R,
Vermylen C, Levine JE. Stem cell transplantation in patients
with severe congenital neutropenia without evidence of
leukemic transformation. Blood. 2000 Feb 15;95(4):1195-8
Carlsson G, Fasth A. Infantile genetic agranulocytosis, morbus
Kostmann: presentation of six cases from the original
"Kostmann family" and a review. Acta Paediatr. 2001
Jul;90(7):757-64
Germeshausen M, Schulze H, Ballmaier M, Zeidler C, Welte K.
Mutations in the gene encoding neutrophil elastase (ELA2) are
not sufficient to cause the phenotype of congenital
neutropenia. Br J Haematol. 2001 Oct;115(1):222-4
Li FQ, Horwitz M. Characterization of mutant neutrophil
elastase in severe congenital neutropenia. J Biol Chem. 2001
Apr 27;276(17):14230-41
References
Dong F, Brynes RK, Tidow N, Welte K, Löwenberg B, Touw IP.
Mutations in the gene for the granulocyte colony-stimulatingfactor receptor in patients with acute myeloid leukemia
preceded by severe congenital neutropenia. N Engl J Med.
1995 Aug 24;333(8):487-93
This article should be referenced as such:
Hess JL. Congenital neutropenia. Atlas Genet Cytogenet
Oncol Haematol. 2002; 6(4):304-305.
Welte K, Dale D. Pathophysiology and treatment of severe
chronic neutropenia. Ann Hematol. 1996 Apr;72(4):158-65
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
305
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Simpson-Golabi-Behmel syndrome
Daniel Sinnett
Division of Hematology-oncology, Research Centre, Sainte-Justine Hospital, 3175 Côte Sainte-Catherine,
Montreal, H3T 1C5, Québec, Canada (DS)
Published in Atlas Database: May 2002
Online updated version: http://AtlasGeneticsOncology.org/Kprones/SimpsonGolabiID10038.html
DOI: 10.4267/2042/37910
This article is an update of:
Punnett HH. Simpson-Golabi-Behmel. Atlas Genet Cytogenet Oncol Haematol 2000;4(4):221
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
mesoderm-derived tissues, and its expression is
downregulated in most adult tissue, implying a
potential role in development. GPC3 is a heparan
sulfate proteoglycan (HSPG) that is attached to the cell
surface via a glycosyl-phosphatidylinositol (GPI)
anchor.
Function: HSPGs of the cell surface are highly
interactive macromolecules playing various roles in cell
migration, proliferation, differentiation and adhesion,
and participating in many developmental and
pathological processes.
Mutations
Germinal: Most cases are caused by deletions of
different exons in the GPC3 genes. The exact role of
GPC3 in the etiology of SGBS is still unknown. The
renal dysplasia observed in both SGBS patients and
GPC3-deficient mice could be explained by the
participation of GPC3 in the control of renal branching
morphogenesis by modulating the actions of several
different growth factors, including BMP2, BMP7 and
fibroblast growth factor 7.
Identity
Inheritance
X-linked with heterogeneity; most families map Xq26;
one large pedigree maps to Xp22.
Clinics
Phenotype and clinics
Characterized by a wide variety of clinical
manifestations including pre-natal and post-natal
overgrowth syndrome
SGBS is phenotypically similar to BeckwithWiedemann syndrome (BWS) suggesting that at least
part of the SGBS phenotype could be due to increased
IGF-II signalling.
Xq26: coarse facieses with mandibular overgrowth,
cleft palate, heart defects, hernias, supernumerary
nipples, renal and skeletal abnormalities.
Xp22: lethal form, multiple anomalies, hydrops fetalis,
death within first 8 weeks of life.
Neoplastic risk
References
Increased risk of embryonal tumors, including Wilms
tumor, neuroblastoma; one case of hepatocellular
carcinoma reported.
Filmus J, Church JG, Buick RN. Isolation of a cDNA
corresponding to a developmentally regulated transcript in rat
intestine. Mol Cell Biol. 1988 Oct;8(10):4243-9
Genes involved and proteins
Hughes-Benzie RM, Hunter AG, Allanson JE, Mackenzie AE.
Simpson-Golabi-Behmel syndrome associated with renal
dysplasia and embryonal tumor: localization of the gene to
Xqcen-q21. Am J Med Genet. 1992 Apr 15-May 1;43(1-2):42835
glypican-3 (GPC3)
Location
Xq26
David G. Integral membrane heparan sulfate proteoglycans.
FASEB J. 1993 Aug;7(11):1023-30
Protein
Description: GPC3 is highly expressed in embryonal
tissues such as the developing intestine and the
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Hughes-Benzie RM, Pilia G, Xuan JY, Hunter AG, Chen E,
Golabi M, Hurst JA, Kobori J, Marymee K, Pagon RA, Punnett
HH, Schelley S, Tolmie JL, Wohlferd MM, Grossman T,
306
Simpson-Golabi-Behmel syndrome
Sinnett D
Schlessinger D, MacKenzie AE. Simpson-Golabi-Behmel
syndrome: genotype/phenotype analysis of 18 affected males
from 7 unrelated families. Am J Med Genet. 1996 Dec
11;66(2):227-34
Brzustowicz LM, Farrell S, Khan MB, Weksberg R. Mapping of
a new SGBS locus to chromosome Xp22 in a family with a
severe form of Simpson-Golabi-Behmel syndrome. Am J Hum
Genet. 1999 Sep;65(3):779-83
Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen
EY, Huber R, Neri G, Cao A, Forabosco A, Schlessinger D.
Mutations in GPC3, a glypican gene, cause the SimpsonGolabi-Behmel overgrowth syndrome. Nat Genet. 1996
Mar;12(3):241-7
Murthy SS, Shen T, De Rienzo A, Lee WC, Ferriola PC,
Jhanwar SC, Mossman BT, Filmus J, Testa JR. Expression of
GPC3, an X-linked recessive overgrowth gene, is silenced in
malignant mesothelioma. Oncogene. 2000 Jan 20;19(3):410-6
Paine-Saunders S, Viviano BL, Zupicich J, Skarnes WC,
Saunders S. glypican-3 controls cellular responses to Bmp4 in
limb patterning and skeletal development. Dev Biol. 2000 Sep
1;225(1):179-87
Eggenschwiler J, Ludwig T, Fisher P, Leighton PA, Tilghman
SM, Efstratiadis A. Mouse mutant embryos overexpressing
IGF-II exhibit phenotypic features of the Beckwith-Wiedemann
and Simpson-Golabi-Behmel syndromes. Genes Dev. 1997
Dec 1;11(23):3128-42
Tumova S, Woods A, Couchman JR. Heparan sulfate
proteoglycans on the cell surface: versatile coordinators of
cellular functions. Int J Biochem Cell Biol. 2000 Mar;32(3):26988
Lapunzina P, Badia I, Galoppo C, De Matteo E, Silberman P,
Tello A, Grichener J, Hughes-Benzie R. A patient with
Simpson-Golabi-Behmel
syndrome
and
hepatocellular
carcinoma. J Med Genet. 1998 Feb;35(2):153-6
DeBaun MR, Ess J, Saunders S. Simpson Golabi Behmel
syndrome: progress toward understanding the molecular basis
for overgrowth, malformation, and cancer predisposition. Mol
Genet Metab. 2001 Apr;72(4):279-86
Li M, Squire JA, Weksberg R. Molecular genetics of
Wiedemann-Beckwith syndrome. Am J Med Genet. 1998 Oct
2;79(4):253-9
Grisaru S, Cano-Gauci D, Tee J, Filmus J, Rosenblum ND.
Glypican-3 modulates BMP- and FGF-mediated effects during
renal branching morphogenesis. Dev Biol. 2001 Mar
1;231(1):31-46
Neri G, Gurrieri F, Zanni G, Lin A. Clinical and molecular
aspects of the Simpson-Golabi-Behmel syndrome. Am J Med
Genet. 1998 Oct 2;79(4):279-83
Pellegrini M, Pilia G, Pantano S, Lucchini F, Uda M, Fumi M,
Cao A, Schlessinger D, Forabosco A. Gpc3 expression
correlates with the phenotype of the Simpson-Golabi-Behmel
syndrome. Dev Dyn. 1998 Dec;213(4):431-9
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
This article should be referenced as such:
Sinnett D. Simpson-Golabi-Behmel syndrome. Atlas Genet
Cytogenet Oncol Haematol. 2002; 6(4):306-307.
307
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in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Fanconi anaemia
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Kprones/FA10001.html
DOI: 10.4267/2042/37911
This article is an update of:
Huret JL. Fanconi anaemia. Atlas Genet Cytogenet Oncol Haematol 1998;2(2):68-69
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
in FA, and it has been assumed that 'it is reasonable to
regard the Fanconi anemia genotype as "preleukemia"';
mean age at diagnosis: 13-15 yrs
Hepatocarcinoma (androgen-therapy induced) in 10%;
mean age at diagnosis: 16 yrs.
Other cancers in 2-5%: in particular squamous cell
carcinoma.
Identity
Alias
Fanconi pancytopenia
Note
Fanconi anaemia is a chromosome instability syndrome
with progressive bone marrow failure and an increased
risk of cancers.
Inheritance
Autosomal recessive; frequency is about 2.5/105
newborns.
Treatment
Androgens and steroids to improve haematopoietic
functions; bone marrow transplantation prevents from
terminal pancytopenia, and from ANLL as well.
Prognosis
Clinics
Mean age at death: 16 years; most patients die from
marrow aplasia (haemorrhage, sepsis), and others from
malignancies; MDS and ANLL in FA bear a very poor
prognosis (median survival of about 6 mths); survival is
also poor in the case of a squamous cell carcinoma.
It has recently been shown that significant phenotypic
differences were found between the various
complementation groups (see below). In FA group A,
patients homozygous for null mutations had an earlier
onset of anemia and a higher incidence of leukemia
than those with mutations producing an altered protein.
FA group G patients had more severe cytopenia and a
higher incidence of leukemia. FA group C patients had
less somatic abnormalities, which, in reverse, were
more frequent in the rare groups FA-D, FA-E, and FAF. FA group G patients patients and patients
homozygous for null mutations in FANCA are highrisk groups with a poor hematologic outcome and
should be considered as candidates both for
Phenotype and clinics
Growth retardation (70% of cases).
Skin abnormalities: hyperpigmentation and/or café au
lait spots in 80%.
Squeletal malformations (60%), particularly radius axis
defects (absent or hypoplastic thumb or radius...).
No immune deficiency (in contrast with most other
chromosome instability syndromes).
Progressive bone marrow failure; mean age of onset of
anemia: 8 yrs; diagnosis made before onset of
haematologic manifestations in only 30%.
Other: renal anomalies, hypogonadism, mental
impairment, heart defects, and perhaps diabetes
mellitus, also occur in 10 to 30% of cases.
Neoplastic risk
Myelodysplasia (MDS) and acute non lyphocytic
leukaemia (ANLL): 15% of cases; i.e. a 15000 fold
increased risk of MDS and ANLL has been evaluated
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
308
Fanconi anaemia
Huret JL
A: gaps; B: breaks; C: deletion; D: triradials; E: quadriradials; F: complex figures; G: dicentric. Giemsa staining - Editor.
Cytogenetics
The most prevalent complementation groups are: group
A (65-70% of cases), groups C and G (10-15% each)
Rare complementation groups are groups B, D, E, and
F (Six genes have been discovered, corresponding to
the frequent phenotypes:
FANCA in 16q24, FANCC in 9q22, and FANCG in
9p13, and to the rarer phenotypes FANCD2 in 3p25.
FANCE in 6p21, and FANCF in 11p15.The genes
FANCB and FANCD1 have yet to be uncovered.
Inborn conditions
To be noted
frequent monitoring and early therapeutic intervention.
There may also be a certain degree of clinical
heterogeneity.according to the degree of mosaicism.
Therefore, clinical manifestations may be variable
within a given family, according to the stage of
embryonic development at which the somatic reverse
mutation occurred.
Spontaneous chromatid/chromosome breaks, triradials,
quadriradials.
Hypersensitivity to the clastogenic effect of DNA
cross-linking agents (increased rate of breaks and radial
figures);
diepoxybutane,
mitomycin
C,
or
mechlorethamine hydrochlorid are used for diagnosis.
Note
Clinical diagnosis may, in certain cases, be very
difficult; cytogenetic ascertainment is then particularly
useful; however, cytogenetic diagnosis may also, at
times, be very uncertain; this is a great problem when
bone marrow engraftment has been decided in a
pancytopenic patient: if this patient has FA, bone
marrow conditioning must be very mild, as FA cells are
very clastogen sensitive. The recent discover of genes
involved in the disease should improve diagnostic
ascertainment.
FA patients (i.e. patients with defective alleles) may
have, in a percentage of cells, a somatic reversion (by
revert mutation towards wild-type gene); such a
phenomenon is also known in Bloom syndrome,
another chromosome instability syndrome.
Cytogenetics of cancer
various clonal anomalies are found in MDS or ANLL
in Fanconi anaemia patients, such as the classical 5/del(5q), and -7/del(7q), found in 10 % of cases;
telomeres appear to be non randomly involved in FA's
clonal anomalies.
Other findings
Note
Slowing of the cell cycle (G2/M transition, with
accumulating of cells in G2).
Impaired oxygen metabolism.
Defective P53 induction.
References
Glanz A, Fraser FC. Spectrum of anomalies in Fanconi
anaemia. J Med Genet. 1982 Dec;19(6):412-6
Genes involved and proteins
Huret JL, Tanzer J, Guilhot F, Frocrain-Herchkovitch C,
Savage JR. Karyotype evolution in the bone marrow of a
patient with Fanconi anemia: breakpoints in clonal anomalies
of this disease. Cytogenet Cell Genet. 1988;48(4):224-7
Note
There are 7 complementation groups (A to G).
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
309
Fanconi anaemia
Huret JL
Auerbach AD, Allen RG. Leukemia and preleukemia in Fanconi
anemia patients. A review of the literature and report of the
International Fanconi Anemia Registry. Cancer Genet
Cytogenet. 1991 Jan;51(1):1-12
Faivre L, Guardiola P, Lewis C, Dokal I, Ebell W, Zatterale A,
Altay C, Poole J, Stones D, Kwee ML, van Weel-Sipman M,
Havenga C, Morgan N, de Winter J, Digweed M, Savoia A,
Pronk J, de Ravel T, Jansen S, Joenje H, Gluckman E,
Mathew CG. Association of complementation group and
mutation type with clinical outcome in fanconi anemia.
European Fanconi Anemia Research Group. Blood. 2000 Dec
15;96(13):4064-70
Strathdee CA, Duncan AM, Buchwald M. Evidence for at least
four Fanconi anaemia genes including FACC on chromosome
9. Nat Genet. 1992 Jun;1(3):196-8
Strathdee CA, Gavish H, Shannon WR, Buchwald M. Cloning
of
cDNAs
for
Fanconi's
anaemia
by
functional
complementation. Nature. 1992 Apr 30;356(6372):763-7
Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers
C, Hejna J, Grompe M, D'Andrea AD. Interaction of the
Fanconi anemia proteins and BRCA1 in a common pathway.
Mol Cell. 2001 Feb;7(2):249-62
Butturini A, Gale RP, Verlander PC, Adler-Brecher B, Gillio AP,
Auerbach AD. Hematologic abnormalities in Fanconi anemia:
an International Fanconi Anemia Registry study. Blood. 1994
Sep 1;84(5):1650-5
Grompe M, D'Andrea A. Fanconi anemia and DNA repair. Hum
Mol Genet. 2001 Oct 1;10(20):2253-9
Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew
CG. Direct interactions of the five known Fanconi anaemia
proteins suggest a common functional pathway. Hum Mol
Genet. 2001 Feb 15;10(4):423-9
Diatloff-Zito C, Duchaud E, Viegas-Pequignot E, Fraser D,
Moustacchi E. Identification and chromosomal localization of a
DNA fragment implicated in the partial correction of the
Fanconi anemia group D cellular defect. Mutat Res. 1994 May
1;307(1):33-42
Qiao F, Moss A, Kupfer GM. Fanconi anemia proteins localize
to chromatin and the nuclear matrix in a DNA damage- and cell
cycle-regulated manner. J Biol Chem. 2001 Jun
29;276(26):23391-6
. Positional cloning of the Fanconi anaemia group A gene. Nat
Genet. 1996 Nov;14(3):324-8
Lo Ten Foe JR, Rooimans MA, Bosnoyan-Collins L, Alon N,
Wijker M, Parker L, Lightfoot J, Carreau M, Callen DF, Savoia
A, Cheng NC, van Berkel CG, Strunk MH, Gille JJ, Pals G,
Kruyt FA, Pronk JC, Arwert F, Buchwald M, Joenje H.
Expression cloning of a cDNA for the major Fanconi anaemia
gene, FAA. Nat Genet. 1996 Nov;14(3):320-3
Yamashita T, Nakahata T. Current knowledge on the
pathophysiology of Fanconi anemia: from genes to
phenotypes. Int J Hematol. 2001 Jul;74(1):33-41
Callén E, Samper E, Ramírez MJ, Creus A, Marcos R, Ortega
JJ, Olivé T, Badell I, Blasco MA, Surrallés J. Breaks at
telomeres and TRF2-independent end fusions in Fanconi
anemia. Hum Mol Genet. 2002 Feb 15;11(4):439-44
D'Andrea AD, Grompe M. Molecular biology of Fanconi
anemia: implications for diagnosis and therapy. Blood. 1997
Sep 1;90(5):1725-36
This article should be referenced as such:
Garcia-Higuera I, Kuang Y, Näf D, Wasik J, D'Andrea AD.
Fanconi
anemia
proteins
FANCA,
FANCC,
and
FANCG/XRCC9 interact in a functional nuclear complex. Mol
Cell Biol. 1999 Jul;19(7):4866-73
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Huret JL. Fanconi anaemia. Atlas Genet Cytogenet Oncol
Haematol. 2002; 6(4):308-310.
310
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Tuberous sclerosis (TSC)
Julie Steffann, Arnold Munnich, Jean-Paul Bonnefont
INSERM U393, Groupe Hospitalier Necker-Enfants Malades, Tour Lavoisier 2, 149 rue de Sèvres, 75743
Paris Cedex15, France (JS, AM, JPB)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Kprones/TuberSclerosID10014.html
DOI: 10.4267/2042/37912
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
- Multiple retinal nodular hamartomas
- Cortical tuber
- Subependymal nodule
- Subependymal giant cell astrocytoma
- Cardiac rhabdomyoma, single or multiple
- Lymphangiomyomatosis
- Renal angiomyolipoma
Minor features:
- Multiple, randomly distributed pits in dental enamel
- Hamartomatous rectal polyps
- Bone cysts
- Cerebral white matter radial migration lines
- Gingival fibromas
- Nonrenal hamartoma
- Retinal achromic patch
- "confetti " skin lesions
- Multiple renal cysts
Identity
Alias
Bourneville disease; Epiloia
Inheritance
Frequency: 1/6000-1/10000 birth. First genetic cause of
epilepsy associated with mental retardation = epiloia.
2/3 of cases are sporadic, 1/3 are inherited.
Genetic heterogeneity: two genes, TSC1 and TSC2,
account for the majority of cases. Somatic mosaicism
has been reported in association with a milder form of
the disease. Germinal mosaicism has been described
and must be taken into account for genetic counselling.
Autosomal dominant with almost complete penetrance
but variable expressivity.
Clinics
Neoplastic risk
Note
Disability in TSC patients most often results from the
involvement of brain. Two types of lesions are static
(hamartias); cortical tubers, and subcortical heterotopic
nodules, whereas subependymal nodules are often
progressive
(hamartoma),
hence
the
term
subependymal giant cell astrocytoma.
Renal angiomyolipomas, often multiple and bilateral,
(75% of children withTSC). occasionnally (< 2-3%),
turn into renal carcinomaonly later in life.
Cardiac rhabdomyomas, often congenital, tend to
regress in infancy, remain identical in same size
through out childhood and can then either again regress
or progress (girls) in adolescence.
Brain tumors, (incidence 5-14%), are mostly (>90%)
subependymal
giant
cell
astrocytomas,
or
ependymomas.
Hamartomas also occur in liver, spleen, and various
tissues.
Pulmonary lymphangiomyomatosis is a destructive
lung disease characterized by a diffuse hamartomatous
proliferation of smooth muscle cells in lungs.
Phenotype and clinics
The definition of the tuberous sclerosis complex
requires either two major features or one major feature
plus two minor features.
Major features:
- Facial angiofibromasor forehead plaque
- Non traumatic ungual or periungual fibroma
- Hypomelanotic macules (three or more)
- Shagreen patch ( connective tissue nevus)
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
311
Tuberous sclerosis (TSC)
Steffann J et al.
No special feature.
Mutations
Germinal: Most TSC1 and TSC2 mutations are
truncating mutations. Both large deletions and missense
mutations are not uncommon at TSC2 locus, whereas
most TSC1 mutations are small truncating lesions.
Somatic: Loss of heterozygosity has been described in
some tumor types, such as angiomyolipomas, giant cell
astrocytomas, or rhabdomyomas, but is rare in cortical
tubers.
Genes involved and proteins
References
Note
Two genes are involved, TSC1 and TSC2.
The patients with TSC1 mutations would have a milder
form of the disease, compared to those with TSC2
mutations.
Kobayashi T, Hirayama Y, Kobayashi E, Kubo Y, Hino O. A
germline insertion in the tuberous sclerosis (Tsc2) gene gives
rise to the Eker rat model of dominantly inherited cancer. Nat
Genet. 1995 Jan;9(1):70-4
Cytogenetics
Inborn conditions
Increased frequency of premature centromere
disjonction (PCD) in cultured fibroblasts, especially for
chromosome 3.
Cytogenetics of cancer
Bosi G, Lintermans JP, Pellegrino PA, Svaluto-Moreolo G,
Vliers A. The natural history of cardiac rhabdomyoma with and
without tuberous sclerosis. Acta Paediatr. 1996 Aug;85(8):92831
TSC1
Location
9q34
Note
Accounts for about 50% of TSC patients.
DNA/RNA
Description : 23 exons.
Protein
Note: Tumor suppressor.
Description: Hamartin and tuberin cohybridize in vivo.
Hamartin is a growth inhibitory protein, affecting cell
proliferation via deregulation of G1 phase, possibly by
regulating cellular adhesion through ezrin-radixinmoiesin family proteins and the small GTP-binding
protein RHO.
Carbonara C, Longa L, Grosso E, Mazzucco G, Borrone C,
Garrè ML, Brisigotti M, Filippi G, Scabar A, Giannotti A, Falzoni
P, Monga G, Garini G, Gabrielli M, Riegler P, Danesino C,
Ruggieri M, Magro G, Migone N. Apparent preferential loss of
heterozygosity at TSC2 over TSC1 chromosomal region in
tuberous sclerosis hamartomas. Genes Chromosomes Cancer.
1996 Jan;15(1):18-25
Au KS, Hebert AA, Roach ES, Northrup H. Complete
inactivation of the TSC2 gene leads to formation of
hamartomas. Am J Hum Genet. 1999 Dec;65(6):1790-5
Jones AC, Shyamsundar MM, Thomas MW, Maynard J,
Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JP.
Comprehensive mutation analysis of TSC1 and TSC2-and
phenotypic correlations in 150 families with tuberous sclerosis.
Am J Hum Genet. 1999 May;64(5):1305-15
Roach ES, DiMario FJ, Kandt RS, Northrup H. Tuberous
Sclerosis Consensus Conference: recommendations for
diagnostic
evaluation.
National
Tuberous
Sclerosis
Association. J Child Neurol. 1999 Jun;14(6):401-7
TSC2
Location
16p13
Note
Accounts for about 50% of TSC patients.
DNA/RNA
Description: 41 exons.
Protein
Note: Tumor suppressor.
Fonctions: as a GTPase activating protein which
activates the Ras-related family of small GTP-binding
proteins such as Rap1 and Rab5. Inhibits the G1/S
transition and promotes entry to the G0 phase. The
Eker rat, a naturally occuring animal model of TSC,
has an autosomal dominant trait of renal cell carcinoma
caused by a germline mutation in the rat TSC2 gene.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Verhoef S, Bakker L, Tempelaars AM, Hesseling-Janssen AL,
Mazurczak T, Jozwiak S, Fois A, Bartalini G, Zonnenberg BA,
van Essen AJ, Lindhout D, Halley DJ, van den Ouweland AM.
High rate of mosaicism in tuberous sclerosis complex. Am J
Hum Genet. 1999 Jun;64(6):1632-7
Cheadle JP, Reeve MP, Sampson JR, Kwiatkowski DJ.
Molecular genetic advances in tuberous sclerosis. Hum Genet.
2000 Aug;107(2):97-114
Mizuguchi M, Takashima S. Neuropathology of tuberous
sclerosis. Brain Dev. 2001 Nov;23(7):508-15
This article should be referenced as such:
Steffann J, Munnich A, Bonnefont JP. Tuberous sclerosis
(TSC). Atlas Genet Cytogenet Oncol Haematol. 2002;
6(4):311-312.
312
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Deep Insight Section
Ataxia-Telangiectasia and variants
Nancy Uhrhammer, Jacques-Olivier Bay, Susan Perlman, Richard A Gatti
Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France (NU, JOB, RAG)
Published in Atlas Database: April 2002
Online updated version: http://AtlasGeneticsOncology.org/Deep/ATMID20006.html
DOI: 10.4267/2042/37913
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Ataxia-telangiectasia (A-T) is an autosomal recessive multisystem disorder with early-onset cerebellar ataxia as its
defining neurologic feature. It is the most common, recessively inherited, cerebellar ataxia in children under 5 years of
age, with a prevalence of 1/40,000 to 1/100,000 live births (Swift, 1985). The accompanying extra-neural features aid in
its clinical diagnosis and include conjunctival and cutaneous telangiectases, elevated levels of serum alpha-fetoprotein,
chromosome aberrations, immunodeficiency with recurrent sinopulmonary infection, cancer susceptibility, and radiation
hypersensitivity. Since identification of the causative gene, ATM (for Ataxia-Telangiectasia mutated), on chromosome
11q22-q23 (Gatti et al., 1988; Savitsky et al., 1995), the molecular basis of certain aspects of the disease have become
clearer, though others remain to be elucidated (Gatti et al., 1998; Meyn, 1997; Shiloh and Rotman, 1996).
Note: see also cards on genes ATM, and NBS1 , and on cancer prone diseases Ataxia telangectasia and Nijmegen
breakage syndrome.
or more diffusely. They do not occur on internal organs
nor are they generally associated with bleeding
problems.
Cancer Risk
Over the course of their lives, nearly 40% of A-T
patients will develop a malignancy (Morrell et al.,
1986). Roughly 85% of these malignancies will be
either leukemia or lymphoma, which in younger
patients may occasionally precede the onset of ataxia.
Children will most often develop acute lymphocytic
leukemia (ALL) of T-cell origin, rather than the pre-B
cell form seen in common childhood ALL. Leukemia
in older A-T patients is usually an aggressive T-cell
process with morphology similar to a chronic
lymphoblastic leukemia (T-CLL, or T-cell prolymphocytic leukemia, T-PLL) (Taylor et al., 1996).
Lymphomas are more often non-Hodgkin's, extranodal, infiltrative, B-cell types, and harder to diagnose
in their early stages (Murphy et al., 1999). Solid tumors
of other tissues occur more commonly as the A-T
patient matures, and are being seen in greater numbers
as these patients are living longer (Morrell, 1968).
CLINICAL FEATURES
Neurologic Features
Progressive cerebellar ataxia is almost always the
presenting symptom and becomes apparent as early as
the first year of life. Truncal and gait ataxia are slowly
and steadily progressive, although between the ages of
2 and 5 years normal development of motor skills may
temporarily mask this decline. This cerebellar
degeneration typically leads to wheelchair dependence
by the second decade. Migration abnormalities of
prenatal Purkinje cell (PC) as well as post-natal PC
degeneration have been seen (Vinters et al., 1985), with
thinning of the molecular and granule cell layers and
minor changes in dentate and olivary nuclei and
medullary tracts. Oculomotor abnormalities may also
be seen. The typical patient with A-T is of normal
intelligence, although the motor abnormalities make
formal psychometric testing and standard learning
programs difficult.
Telangiectasia
Telangiectases appear an average of two to four years
after onset of the neurologic syndrome and are
progressive. They are composed of dilated capillaries in
the conjunctiva, and, later, on the ears, over the bridge
of the nose, in the antecubital fossae, behind the knees,
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Radiosensitivity
313
Ataxia-Telangiectasia and variants
Uhrhammer N et al.
Treatment of A-T patients with cancer with
conventional doses of ionizing radiation results in lifethreatening sequelae characteristic of much higher
doses. In vitro, fibroblasts and lymphoblasts from A-T
homozygotes show sensitivity to a number of
radiomimetic and free-radical-producing agents (Taylor
et al., 1985; Shiloh et al., 1985). This finding led to the
development of the highly sensitive and reasonably
specific diagnostic test, the colony survival assay
(CSA) (Huo et al., 1994).
Recurrent infectious disease
Moderate cellular and humoral immunodeficiency, with
low levels of certain immunoglobulin classes, in
conjunction with difficulties in swallowing, lead to
frequent pulmonary infections in A-T patients. The
incidence and severity of infections varies widely
between patients, with some being severely affected,
while others have no particular difficulty.
Other clinical features
A-T, as in other syndromes manifesting chromosomal
instability (e.g., Fanconi anemia, xeroderma
pigmentosum xeroderma pigmentosum, Bloom
syndrome), shows progeroid features (Gatti and
Walford, 1981). Young A-T patients may have strands
of gray hair or keratoses and basal cell carcinomas.
These signs may be related to the accelerated telomeric
shortening mentioned above, to increased tissue
turnover, and/or to the exaggerated effects of oxidative
damage.
Endocrine defects typically result in gonadal
abnormalities. Most female patients ultimately begin
regular menstrual cycles, but may enter menopause
prematurely. Most male patients develop normal
secondary sexual characteristics. Retardation in somatic
growth is seen in about 75%. Pituitary function studies
show no consistent abnormalities. Some patients
develop insulin-resistant diabetes in their late teens,
with hyperglycemia without glycosuria or ketosis,
possibly due to a particular IgM antibody directed
against insulin receptors (Gatti and Walford, 1981).
BIOLOGICAL FEATURES
AFP levels are usually elevated, and are a reliable
clinical marker after the age of 2. The high levels of
AFP are felt to be of hepatic origin and may be
accompanied by elevations of other liver enzymes, with
no evidence of liver disease at postmortem (Ishiguro et
al., 1986; Gatti and Walford, 1981; McFarlin et al.,
1972).
Virtually all A-T homozygotes that have come to
postmortem examination have a small, embryonic
thymus, but the resulting immunodeficiencies can be
quite variable, even within the same family, suggesting
a problem with maturation of B and T cell precursors.
IgA, IgE, and IgG2 deficiencies are most common,
with the accompanying risk of recurrent sinopulmonary
infection (Roifman and Gelfand, 1985). Elevated serum
IgM levels may occasionally progress to a high blood
viscosity syndrome, with splenomegaly, lymphoadenopathy, neutropenia, thrombocytopenia, and
congestive heart failure. T-cell deficiencies occur in
half the patients, with abnormal skin test antigen and
PHA responses (Paganelli et al., 1992). In a British
study of 70 patients (Woods and Taylor, 1992), 10%
had severe immunodeficiencies, while nearly 40% had
normal immunologic function.
CLINICOPATHOLOGY OF THE A-T
HETEROZYGOTE
The carrier frequency for ATM is estimated at 1%.
Carriers are normal neurologically, although they have
in vitro radiosensitivity values that are intermediate
between homozygotes and normals (Taylor et al., 1985;
Paterson et al., 1985; Weeks et al., 1991). It remains
unclear whether this translates to any greater risk
during exposure to ionizing radiation clinically
(diagnostic X-rays, radiation therapy), although results
from Broeks suggest that A-T heterozygotes are more
frequent among breast cancer patients who develop a
second breast tumor after radiotherapy (Broeks et al.,
2000). Studies of mice heterozygous for Atm show an
increased frequency of dysplastic breast cells in
irradiated animals, supporting an increased cancer risk
for heterozygotes that is related to their mutagen
exposure (Weil et al., 2001). These data suggest that
perhaps Swift's recommendation that female relatives
of A-T patients avoid mammography is good advice,
although the benefit drawn from early detection is
largely thought to outweigh the very small chance that
the screening could actually provoke a breast tumor,
especially when up-to-date mammography equipment
with the lowest possible dose is used. Excessive
numbers of ATM heterozygotes have not been
identified among patients over-reacting to radiotherapy,
nor have ATM heterozygotes diagnosed with cancer
been noted to have unusual reactions to irradiation,
CYTOGENETIC FEATURES
Karyotyping of peripheral lymphocytes from A-T
homozygotes
shows
nonrandom
chromosomal
rearrangements
which
preferentially
involve
chromosomal breakpoints at 14q11, 14q32, 7q35, 7p14,
2pll, and 22q11, and correlate with the regions of the Tcell and B-cell receptor gene complexes (Aurias, 1986).
Telomere shortening and fusions, with normal
telomerase activity (Pandita et al., 1995), have been
observed in peripheral blood lymphocytes of A-T
patients, especially in pre-leukemic T-cell clones
(Metcalfe et al., 1996).
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
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Ataxia-Telangiectasia and variants
Uhrhammer N et al.
cancer cases than in the healthy population (Gatti et al.,
1999). These changes include missense and silent
mutations as well as nucleotide changes in the introns.
Although some of these will certainly turn out to be
innocuous polymorphisms, others may indeed be
associated with reduced or altered function of the ATM
protein.
Loss of heterozygosity (LOH) at the ATM locus has
been found in 30 to 60% of cancers, (Hampton et al.,
1994; Rio et al., 1998; Uhrhammer et al., 1999),
suggesting that ATM may have a role in tumorigenesis,
although it is difficult to interpret this type of study due
to the large region of chromosome 11q that may be
involved in the LOH, and the fact that genes near to
ATM may also be involved. In addition, in breast and
colon cancer the incidence of LOH at the ATM locus is
not very much higher than background.
The demonstration of the inactivation of the ATM
protein in tumors would more precisely define its
importance. A few cases have been described, where
the wild-type allele of ATM is inactivated in the tumor
tissue of a heterozygote, but the loss of ATM has not
been described generally in breast oncogenesis (Chen
et al., 1998; Vorechovsky et al., 1996b; Bay et al.,
1999). More definitive studies using antibodies against
ATM on tumor tissue sections are underway in several
laboratories.
Somatic mutations of both alleles of ATM have been
found in T-prolymphocytic leukemia, in mantle cell
lymphoma and in chronic B-lymphoid leukemias,
suggesting that in these types of malignancy ATM does
play a tumor-suppressor role (Vorechovsky et al., 1998;
Stankovic et al., 1999; Bullrich et al., 1999; Shaffner et
al., 2000). This is an interesting finding, because
although A-T homozygotes are prone to these types of
cancer, they have not been described in A-T
heterozygotes.
suggesting that their radiosensitivity in vivo is not great
(Clarke et al., 1998; Hall et al., 1998).
CANCER RISK OF AT CARRIERS
Several authors have reported that the incidence of
cancer in A-T heterozygotes was higher than that in the
general population, most notably breast cancer in
female heterozygotes less than 60 years of age (Swift et
al., 1991; Pippard et al., 1988; Borreson et al., 1990).
Other cancers were also mentioned, such as stomach
and liver cancer (Swift et al., 1991; Chessa et al.,
1994). Several authors now agree that the relative risk
of breast cancer in heterozygotes is between 3.3 and 3.9
(Easton, 1994; Inskip et al., 1999; Athma et al., 1996;
Janin et al., 1999), with a greater RR at younger ages
and no significantly increased risk above age 60, while
the relative risk for other types of cancer is not
elevated. This modest risk, however, may correspond to
a significant percentage of breast cancer in the
population at large being attributable to heterozygosity
at ATM: if 1% of the population is heterozygous at
ATM, and the RR of breast cancer is about 3, then 2 to
4% of new breast cancer cases may be due to defects in
ATM.
A few groups have searched for constitutional ATM
mutations in circulating lymphocytes from sporadic
breast cancer cases, and have not found an increased
carrier frequency (Fitzgerald et al., 1996; Bebb et al.,
1999). Thus, it seems that heterozygosity for ATM is
not associated with a tendency toward breast cancer,
even though family studies indicate increased risk.
There may be several reasons for this discrepancy, first,
PTT only identifies 60 to 70% of mutations in A-T
homozygotes, and these are not necessarily
representative of those associated with breast cancer
(Telatar et al., 1996). Secondly, the frequency of A-T
heterozygotes in the population is not well defined,
although 1% is often cited (Swift et al., 1986; Easton,
1994). Therefore, the low numbers of constitutional
mutations found in the above studies do not exclude a
role for ATM in breast cancer. Larger study
populations and more sensitive techniques to detect
ATM mutations are needed before any significant
difference between the study and control groups can be
reliably defined.
Other groups have looked for ATM mutations in
familial breast cancer familial breast cancer, again
without finding excessive numbers of constitutional
heterozygotes (Vorechovsky et al., 1996a; Bay et al.,
1998; Chen et al., 1998). It is in fact unlikely that
heterozygosity for ATM would lead to identifiable
cancer families, due to the low relative risk involved.
Although the truncating mutations found in A-T
patients have not been found frequently in breast cancer
patients, it is curious that small changes in the ATM
sequence are found much more frequently in breast
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
STRUCTURE AND FUNCTION OF
THE ATM PROTEIN
The gene:
The ATM gene occupies ~150 kb of 11q22.3-q23.1
(Platzer et al., 1997) (Fig1). ATM is transcribed from a
bi-directional promoter that also drives expression of
the NPAT/Cand3/E14 gene (Platzer et al., 1997; Imai et
al., 1997), although the significance of this coexpression is unknown. There are also two alternative
exons 1, although differential expression of the mRNA
isoforms in different tissues or in response to different
stimuli has not been described, nor is there any change
in the amino acid sequence of the resulting protein,
since translation is initiated in exon 3. The 13 kb ATM
mRNA, with its 9168 bp of coding sequence, appears
to be expressed in most tissues and stages of
development (Savitsky et al., 1995).
315
Ataxia-Telangiectasia and variants
Uhrhammer N et al.
Figure 1: The ATM gene at 11q22.3-q23.1 is transcribed from a bodirectional promoter. Microsatellite loci are found in introns 25 (NS22)
and 63 (D11S2179).
S phase arrest: the phosphorylation of cAbl also
serves to halt progression within S phase by inhibiting
Rad51Rad51, a single-stranded DNA binding protein
essential for replication. Replication Protein A (RPA),
another protein essential for the progression of DNA
replication, is inhibited by ATM through phosphorrylation of its 34 kDa subunit. ATM has been shown to
phosphorylate Ser222 of the FANCD2 protien, which is
essential for S phase arrest in response to treatment
with DNA cross-linking agents (Grompe and D'Andrea,
2001). Two authors have shown that ATM is not,
however, required for the decatenation checkpoints in S
phase or late G2 phase, underlining the existence of
multiple checkpoints throughout the cell cycle
(Montecucco et al., 2001; Deming et al., 2001).
Abnormalities in S phase lead to the quantifiable
phenotype known as ‘radiation resistant DNA
synthesis’, or RDS in cells from A-T homozygotes.
G2 cell cycle arrest: ATM inhibits cells from entering
mitosis after irradiation through the phosphorylation of
at least two targets, Chk1 and Chk2. The literature is
occasionally indistinct on the subject of G2 arrest in AT cells, most likely because there are two arrest points,
and only one is defective in A-T. Immediately after
DNA damage, the defective cell cycle checkpoint can
be measured as a failure to diminish the numbers of
cells that enter mitosis in the hours that follow
irradiation. In contrast, at later times there is clearly an
increase in G2 cells which is readily detectable by
FACS analysis. This late G2 accumulation is due to
cells that were in G1 or S at the time of irradiation,
which replicated their DNA in spite of the presence of
DSBs, and which have now triggered a distinct G2
checkpoint.
ATM and radiation-induced apoptosis:
Radiosensitivity is a constant feature of A-T and is
thought to be due to excessive apoptosis. How ATM
inhibits apoptosis is not completely understood, and
may be different according to the type of tissue studied.
One route is through the phosphorylation of IkB. IkB is
an inhibitor of NFkB, and its phosphorylation leads to
the release of NFkB sequestered in the cytoplasm.
NFkB now translocates to the nucleus, where it acts as
a transcriptional regulator of anti-apoptotic genes. A
second level of apoptosis control acts through p53,
Notably, expression does not vary with the cell cycle or
increase in response to irradiation (Brown et al., 1997).
Homologs of ATM have been identified in other
mammals and in fish and amphibians, though no true
yeast homolog has been identified. Several proteins
with homology to ATM have been found, including the
catalytic subunit of DNA-PK and ATR. The greatest
similarity between these proteins is in the kinase
domain, and together they form a sub-family of PI3kinase-related proteins.
The protein:
The 350 kDa ATM protein contains a leucine zipper, a
domain with homology to the S. pombe Rad3 protein,
and a protein kinase domain homologous to the PI3K
family (Chen and Lee, 1996). ATM is localized mostly
to the nucleus, but is also found in cytoplasmic vesicles
(Chen and Lee, 1996; Gately et al., 1998; Watters et al.,
1997). ATM has been shown to associate with DNA,
with particular affinity for DNA ends (Smith et al.,
1999). This DNA end-binding activity suggests that
ATM might be the/a primary sensor of DNA doublestrand breaks (DSBs). In the presence of DNA DSB
damage, ATM phosphorylates a variety of protein
targets and activates several different signaling
cascades (Figure 2). In contrast to the mRNA, ATM
protein does become more abundant in response to IR,
although only in cells such as lymphocytes that express
low basal levels: no change is seen in cells expressing
high levels of ATM (Fang et al., 2001). In addition,
ATM becomes more tightly attached to the nuclear
matrix and/or chromatin in the presence of DNA
damage (Andegeko et al., 2001).
G1 cell cycle arrest: ATM induces G1 phase arrest
through the action of several intermediates. One of the
most important targets is the phosphorylation of p53 on
ser15 (Canman et al., 1998; Khanna et al., 1998;
Watterman et al., 1998). Among the genes whose
transcription is induced by p53 is the cdk-inhibitor
p21Waf1/Cip1 p21Waf1/Cip1, which plays a key role in
inhibiting the transition from G1 to S phase.
ATM also induces G1 arrest through the
phosphorylation of cAbl (Shafman et al., 1997;
Baskaran et al., 1997), which in turn activates both the
p53 homolog p73 and the SAPK pathway to block
progression to S phase.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
316
Ataxia-Telangiectasia and variants
Uhrhammer N et al.
Figure 2. In response to DNA double-strand breaks, ATM interacts with many different proteins to induce cell cycle arrest, increase DNA
repair, and inhibits apoptosis.
though the mechanism is likely to be indirect. Cultured
A-T fibroblasts undergo apoptosis in response to
irradiation, and this process may be inhibited by the
inactivation of p53. As we have seen, ATM activates
the cell cycle arrest functions of p53, but it is as yet
unknown how the inhibition of p53’s pro-apoptotic
functions works. It is possible that ATM-/- cells allow
replication of damaged DNA templates, which in turn
trigger p53 through independent mechanisms.
A third pathway through which ATM inhibits apoptosis
might be through the ceramide synthesis cascade. This
signaling cascade is initiated at the cell membrane in
response to irradiation, and is dysregulated in A-T
cells. It is not yet known how ATM is involved, and
whether the detection of DNA damage is necessary or
if ATM might detect some other damage signal.
Most of the functions described above take place in the
nucleus, where ATM surveys the DNA for DSBs, and
phosphorylates its substrates when necessary. The
phosphorylation of IkB (and possibly of cAbl) occurs
in the cytoplasm, however, and the proteins of the
ceramide signaling pathway are located on membranes
accessible from the cytoplasm. Some authors have
proposed that the pool of ATM associated with
cytoplasmic vesicles performs functions distinct from
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
genomic surveillance. ATM has been shown to
associate with beta-adaptin in the cytoplasm and may
be involved in vesicle trafficking and intercellular
communication, and it is this aspect which may
eventually explain the specific degeneration of
cerebellar Purkinje cells.
ATM and DSB repair
A-T cells exhibit subtle defects in DSB repair: they
take longer to repair DSBs and the repair of plasmid
substrates is often inexact. While ATM itself does not
seem to play a direct role in the rejoining of DSBs, it is
involved in the control of this process. As we have
seen, ATM activates GADD45 indirectly though p53.
In addition, BRCA1 has been shown to be
phosphorylated by ATM in response to DSBs and this
phosphorylation is essential to relieve the radiation
sensitivity of BRCA1-mutant cells (Cortez et al., 1999).
BRCA1 has been described as being necessary for the
aggregation
of
Rad51
complexes
or
Rad50/Mre11/nibrin at DSB sites, in addition to being
a transcriptional activator. Rad50 and Rad51 are both
required for the repair of DSBs, and BRCA1 may
provide a link in the signaling cascade that activates
repair. Finally, ATM probably activates DSB repair
through Rad50/Mre11/nibrin independently from
317
Ataxia-Telangiectasia and variants
Uhrhammer N et al.
intermediate between that of A-T patients and normal
subjects. Intriguingly, these cellular phenotypes of
ATLD are identical to those of NBS patients, even
though the neural phenotypes are different (there being
no micro-cephaly or mental retardation in ATLD, nor
cerebellar ataxia in NBS). Recall that NBS patients
have mutations in the gene encoding nibrin, a subunit
of Rad50/Mre11/nibrin.
The four patients described with hMre11 mutations are
two homozygotes for a nonsense mutation at codon
633, and two compound heterozygotes for a null
mutation and a substitution of serine for asparagine at
amino acid 117. Both the nonsense and missense
mutated proteins produce stable products that are able
to associate with Rad50 and nibrin, although the
aggregation of this complex at DSB sites is abnormal.
Data from mMre11 knockout mice indicate that these
human mutations are most likely to be partially
functional, because a null allele of mMre11 is lethal
during embryogenesis, as are null alleles for mRad50
(mice with Nbs1 mutations have are similar to Atm-/mice, with growth retardation, lymphoid developmental
defects, lymphoid thymomas, radiosensitivity and
female - though not male - sterility) (Xiao and Weaver,
1997; Kang et al., 2002).
The interaction between ATM and Mre11 is becoming
more clear. The Rad50/Mre11/nibrin complex has
described as containing (an) additional protein(s) of
high molecular weight, and probably associates loosely
or transiently with several other proteins, including
BRCA1 and ATM. Clearly, ATM, Mre11, nibrin, and
BRCA1 are all required for the aggregation of Rad50 at
DSB sites. ATM phosphorylates both nibrin and
Mre11, and in the absence of nibrin, ATM fails to
phosphorylate Mre11 (Wu et al., 2000; Kim et al.,
1999). Rad50, Mre11, and the yeast analog of nibrin,
xrs5, all perform essential repair functions and their
loss is lethal. The loss of regulatory proteins such as
ATM or BRCA1, or the reduced function of nibrin or
Mre11 is tolerated but decreases the efficiency of
repair.
How do the known molecular functions of ATM
explain the disease?
1. Radiosensitivity: without ATM, DNA damage
triggers
apoptosis
in
sensitive
cell
types.
Radiosensitivity is not due to acquired mutations and
karyotypic inviability, but to programmed cell
elimination.
2. Cancer risk: A-T cells either create or tolerate
chromosomal rearrangements more than other cells.
These rearrangements may hit genes critical for normal
cell growth and thus initiate cancer. The lack of ATM
is not directly tumorigenic, but rather allows other
mutation events. The stereotypical chromosomal
rearrangements seen in A-T lymphocytes are evidence
of this problem with genomic stability. A new study in
Atm-/- mice, however, showed that spontaneous
BRCA1. Two groups have now shown that ATM
phosphorylates H2AX within seconds of DSB damage
(Burma et al., 2001; Andegeko et al., 2001). H2AX-P
promotes chromatin decondensation and is a major
signal for DNA repair. The speed of this
phosphorylation also provides more circumstantial
evidence for ATM as an actual sensor of DSBs,
although there is as yet no direct evidence for this.
Cells experiencing DSB damage in G1 or G0 repair this
damage through non-homologous end joining, a
process controlled by DNA-PK. The relationship
between ATM and DNA-PK is as yet unclear, since the
abundant Ku subunits of DNA-PK can bind to DNA
ends on their own and recruit DNA-PKcs to the sites
for repair. This temporal difference in the choice of
DSB repair mechanism may be the main reason why
two apparently redundant mechanisms are both
essential, another being that some are unrepairable by
NHEJ due to the poor quality of the DNA ends. In any
case, Atm-/-/SCID double-knockout mice are inviable
after 12 days gestation (Gurley 2001), demonstrating
the additive effect of these two DSB signaling/repair
proteins. Ku70 has been shown now to be essential for
the binding of the Rad50 / Mre11 / nibrin complex at
DSB sites, however, and the similarities of the cellular
phenotypes of A-T and NBS (nibrin-deficient) cells
suggests that this may provide the link between ATM
and DNA-PK. Cells experiencing DSB damage in G2
favor homologous recombination between sister
chromatids for repair.
ATM and Mre11:
Since the cloning of ATM, the vast majority of A-T
patients have been found to carry mutations in the ATM
gene. There are a few cases, however, where no
mutation was detectable in the gene, and the ATM
protein was present in cellular extracts. Stewart has
now described mutations in the hMre11a gene in four
such patients from two families (1999). Interestingly,
cell fusion experiments in the 1980’s indicated that
there were four complementation groups for A-T
(Jaspers et al., 1988). After the cloning of ATM, it was
shown that mutations in this one gene were present in
all four ‘complementation groups’, sometimes identical
mutations, and the multigenic theory of A-T was
essentially discarded as an experimental artifact
(Savitsky et al., 1995). The hMre11a gene is located
about 30 cM proximal to ATM on the long arm of
chromosome 11, at band q22.1.
The phenotypes of human patients with ATM and
hypomorphic hMre11 mutations are very nearly
identical. ATLD patients (for ataxia-telangiectasia-like
disorder) may have a slightly milder phenotype than AT patients, but still within the range of phenotypes
found for classic A-T patients. The phenotypic
differences are apparent at the cellular level: the
induction of p53 is nearly normal, and clonogenic
survival and radioresistant DNA synthesis curves are
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
318
Ataxia-Telangiectasia and variants
Uhrhammer N et al.
mutation rates were not increased in samples of ear and
spleen tissue, suggesting that not all tissues are equally
sensitive to the effects of ATM loss (Turker et al.,
1999).
3. Immunodeficiency: without ATM, the process of
V(D)J recombination is not properly supervised, and
aberrant chromosomes are created. Most cells
recognize the anomaly and commit suicide (leading to
the hypoplastic thymus), but others escape this control
and are detected as circulating lymphocytes carrying
the 7;7, 7;14, and 14;14 rearrangements characteristic
of A-T. That the immunodeficiency in A-T is not as
severe as other syndromes reflects the ability of A-T
cells to create functional V(D)J recombination events at
reduced frequency.
4. Cerebellar degeneration: this aspect of A-T is as yet
unexplained by the known molecular functions of the
protein, though several theories have been advanced. 1)
aberrant migration of Purkinje cells 2) oxidative
damage leads to cell death; 3) an autoimmune process
destroys the Purkinje cells. An excess of oxidative
stress in the cerebellum (and elsewhere) is currently the
favored hypothesis for this degeneration (Stern et al.,
2002).
TREATMENT OF A-T
At present there is no definitive gene-based therapy,
neuroprotective therapy, or neural-restorative therapy
to halt or reverse progression of the neurologic
symptoms of A-T. The extraneural symptoms have
many conventional treatment options, especially in the
important areas of pulmonary infection and
malignancy. Infection is usually with common
microbes, not opportunistic organisms (despite the
combined immuno-deficiency), so prompt treatment
with appropriate antibiotics and attention to aggressive
pulmonary hygiene can prevent future complications
(resistant infections, bronchiectasis, chronic respiratory
failure, and aspiration).
Regular physical examinations with blood counts and
blood chemistries can serve as an early screen for
leukemia/lymphoma and other cancers. Routine pelvic
exams and breast exams in young women, prostate
screening in young men, and skin exams in both should
be instituted. Non-radiologic imaging studies should be
used when any area of concern is raised (MRI,
ultrasound). Should a malignancy occur, treatment
protocols utilizing lower doses of radiation therapy and
alternatives to radiomimetic and neurotoxic agents
should be sought, and chemotherapy protocols with a
high risk of developing a second malignancy
(topoisomerase inhibitors) should be modified. Young
children presenting with leukemia or lymphoma, or any
other malignancy, should be screened for the presence
of A-T before a treatment regimen is begun. Because of
the extreme cancer susceptibility of these patients, they
should be encouraged to avoid excess sun exposure by
keeping skin covered and wearing a hat and sunscreen
when outdoors.
Neurorehabilitation strategies and symptomatic
medication can improve neurologic performance and
reduce the risk of long-term complications from
increasing immobility (deconditioning, contractures,
decubiti, pneumonia, bladder infections, and
constipation). Physical therapy can help the patient
maintain independence, continue in school, and enjoy
leisure pursuits with family and friends. Pool exercise,
speech therapy, remedial learning programs, and
appropriate adaptive equipment also reduce the
ultimate handicaps of these patients.
Most A-T patients in the United States and Western
Europe live well beyond 20 years, thanks to improved
health maintenance and rehabilitation options. This is a
major change from just a few years ago, when it was
unusual for patients to live past their teens, but much
work still needs to be done.
GENOTYPE/PHENOTYPE
CORRELATIONS
Over 300 disease-causing ATM mutations have been
identified, extending over each of the 66 exons, and
patients from non-consanguineous families are
typically compound heterozygotes. Although founder
effect mutations account for significant proportions of
A-T patients in various ethnic populations, they do not
account for significant numbers of A-T patients in
heterogeneous populations such as the United States.
A-T variants, who do not meet all the clinical criteria
for A-T (i.e., relatively late-onset of ataxia or chorea,
unusually long survival, absence of telangiectases,
normal AFP levels, normal immune status, intermediate
levels of radiosensitivity) have been shown for the most
part to have ATM mutations. These have been homo- or
at least heterozygous for milder missense, splice-site,
or small, non-critical insertion/deletion abnormalities
that could allow production of up to 17% of normal
ATM protein. Nonsense, frame-shift, or in-frame
changes, causing two truncating mutations, with
production of little or no ATM protein in over 85% of
patients, result in the more typical A-T phenotype with
lower mean survivals.
Many other patients with phenotypes typical of A-T
(DiRocco, 1999; Hernandez et al., 1993) have not been
shown to have mutations in the ATM gene, and may
represent mutations in other genes that interact with the
ATM protein. One of these proteins has been identified
as Mre11, as discussed above.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
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Stewart GS, Maser RS, Stankovic T, Bressan DA, Kaplan MI,
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This article should be referenced as such:
Uhrhammer N, Bay JO, Perlman S, Gatti RA. AtaxiaTelangiectasia and variants. Atlas Genet Cytogenet Oncol
Haematol. 2002; 6(4):313-322.
Broeks A, Urbanus JH, Floore AN, Dahler EC, Klijn JG,
Rutgers EJ, Devilee P, Russell NS, van Leeuwen FE, van 't
Veer LJ. ATM-heterozygous germline mutations contribute to
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Am
322
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Educational Items Section
Genetic Linkage Analysis
Françoise Clerget-Darpoux
Unité de Recherche d'Epidémiologie Génétique, INSERM U535, Kremlin-Bicêtre, France (FCD)
Published in Atlas Database: May 2002
Online updated version: http://AtlasGeneticsOncology.org/Educ/LinkageLongID30031EL.html
DOI: 10.4267/2042/37914
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
I- Genetic linkage analysis
I-1. Recombination fraction
I- 2. Definition of the "lod score" of a family
I- 3. Test for linkage
I- 4. Estimation of the recombination fraction
I- 5. Recombination fraction for a disease locus and a marker locus
I- 6. Linkage analysis for three loci : the phenomenon of interference
I- 7. References
II- Genetic heterogeneity of localization
II- 1. The "Predivided sample test"
II- 2. The "Admixture Test"
II- 3. Generalization of the "admixture test"
II- 4. References
III- Statistical properties of the method of lod scores
III- 1. The test procedure
III- 1.1. Impact of non-sequentiality
III- 1.2. Maximization of the lod score over the [0, 1/2] interval
III- 1.3 References
III-2. Genotype information
III-2.1. Ambiguity in phenotype-genotype relationships at the disease locus
III-2.2. Ambiguity in the marker genotype
III-2.3. Gamete disequilibrium between alleles at the disease locus and at the
marker locus
III-3. The problem of multiple tests
III-4. References
reflected in the recombination fraction, θ which is the
percentage of the gametes transmitted by the parents to
be recombined. If they are transmitted independently,
there will be the same number of recombined gametes
as there are parental gametes, and so θ = 1/2. If they are
I- Genetic linkage analysis
Investigating the linked segregation of genes situated at
different loci is a way of testing the independence of
their transmission. This concept of independence is also
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
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Genetic Linkage Analysis
Clerget-Darpoux F
not transmitted independently, then the parenteral
gametes are transmitted preferentially to the
recombined gametes, and 0≤ θ<1/2. In this case, there
is said to be "linkage" between the two loci.
I-1. Recombination fraction
Let us consider the caseof two loci, A and B, with two
codominant alleles at each of these loci, A1, A2 and B1,
B2 respectively. Such an individual can produce four
types of gamete:
A1B1
A2B1
A1B2
A2B2
Two situations are possible:
Figure 3
Gametes A1B1 and A2B2 are said to be "parental". In
the offspring, as in the parents, A1 is "coupled" with B1
(and A2 is "coupled" with B2).
The gametes A1B2 and A2 B1 are therefore described as
being "recombined". An uneven number of
recombination or "crossing-over" phenomena have
occurred between the A and B loci.
The proportion of recombined gametes amongst the
gametes
transmitted
is
known
as
the
“recombination fraction”.
1- The loci A and B are on different chromosome pairs
θ = number of recombined gametes/number of
gametes transmitted
Assuming that the crossing-over event for a pair of
chromosomes follows Poisson’s law, and knowing that
a parental gamete has zero or an even number of
crossings-over, whereas a recombined gamete has an
odd number, we can show that the frequency of
recombined gametes is always equal to or lower than
that of the parenteral gametes and so 0 ≤ θ < 1/2
If θ = 1/2, then all the gamete types have the same
probability and the alleles at the loci A and B loci are
transmitted independently. Loci A and B are therefore
said not to enhibit genetic linkage. This is the situation
if A and B are on different pairs of chromosomes, and
also if A and B are one the same pair, but at some
distance from each other. However, if θ < 1/2, then the
two loci are genetically linked. For a couple of which
the genotypes at the A and B are known, the probability
of observing the genotypes of the offspring depends on
the value of θ. Let us assume the following crossing:
Figure 1
In this case, the four gametes all have the same
probability: 1/4.
2- The loci A and B are on the same chromosome pairs
Here we have to distinguish between two possible
situations: the alleles A1 and B1 may be on the same
chromosome within the pair, in which case A1 and B1
are said to be "coupled"; or they may be on different
chromosomes, in which case A1 and B1 are said to be in
a state of "repulsion".
Figure 2
For instance, let us suppose that A1 and B1 are
"coupled". Four types of gametes are still produced.
Figure 5
Therefore, such a couple can have 4 types of offspring
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
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Genetic Linkage Analysis
Clerget-Darpoux F
Take a family of which we know the genotypes at the
A and B loci of each of the members. Let L(θ) be the
liklihood of a recombination fraction 0 ≤ θ < 1/2
L(1/2) be the liklihood of θ = 1/2, that is of
independent segregation into A and B.
The lod score of the family in θ is:
Z(θ) = log10 [L(θ)/L(1/2)]
Z can be taken to be a function of θ defined over the
range [0,1/2].
Lod score of a sample of families
The liklihood of a value of θ for a sample of
independent families is the product of the liklihoods of
each family, and so the lod score of the whole sample
will be the sum of the lod scores of each family.
Figure 6
Assuming that there is gamete equilibrium at the A and
B loci, in parent 1 there is a probability of 1/2 that
alleles A1 and B1 will be coupled, and a probability of
1/2 that they will be in repulsion.
(1) A1 and B1 are coupled, so the probability that
parent (1) provides the gametes A1B1 and A2B2 is (1θ)/2 and the probability that this parent provides
gametes A1B2 and A2B1 is θ/2. The probability that the
couple will have child of type (1) or (2) is (1-θ)/2, and
that of their having a type (3) or type (4) child is θ/2.
The probability of finding n1 children of type (1), n2 of
type (2), n3 of type (3) and n4 of type (4) is therefore
[(1- θ)/2]n1+n2 x (θ/2)n3+n4
(2) A1 and B1 are in a state of repulsion, so the
probability that parent (1) provides the gametes A1B2
and A2B1 is (1-θ)/2 and the probability that this parent
provides gametes A1B1 and A2B2 is θ/2.
The probability of the previous observation is
therefore:
(θ/2)n1+n2 x[(1-θ)/2]n3+n4
So in the end, with no additional information about the
A1 and B1 phase, and assuming that the alleles at the A
and B loci are in a state of coupling equilibrium, the
probability of inding n1, n2, n3 and n4 children in
categories (1), (2), (3), (4) is: p(n1,n2,n3,n4/θ)=1/2{[(1 θ)/2]n1+n2 x (θ/2)n3+n4 + (θ/2) n1+n2 x [(1-θ)/2] n3+n4} So the
liklihood of θ for an observation n1, n2, n3, n4 can be
written:
L(θ/n1,n2,n3,n4)=1/2 {[(1-θ)/2]n1+n2 (θ/2)n3+n4 + (θ/2)
n1+n2
[(1-θ)/2] n3+n4}
Special case: number of children n= 1
Regardless of the category to which this child belongs
L(θ) = 1/2 [(1-θ)/2] + 1/2 [θ/2] = 1/4
The liklihood of this observation for the family does
not depend on θ. We can say that such a family is not
informative for θ.
Informative families
An "informative family" is a family for which the
liklihood is a variable function of θ. One essential
condition for a family to be informative is, therefore,
that it has more than one child. Furthermore, at least
one of the parents must be heterozygotic.
Definition: if one of the parents is doubly heterozygotic
and the other is:
- A double homozygote, we have a backcross
- A single homozygote, we have a simple backcross
- A double heterozygote, we have a double intercross
I- 3. Test for linkage
Several methods have been proposed to detect linkage:
"U scores", were suggested by Bernstein in 1931, "the
sib pair test" by Penrose in 1935, "likelihood ratios" by
Haldane and Smith in 1947, "the lod score method"
proposed by Morton in 1955 (1). Morton’s method is
the one most commonly used at present.
The test procedure in the lod score method is sequential
(Wald, 1947 (2)). Information, i.e. the number of
families in the sample, is accumulated until it is
possible to decide between the hypotheses H0 and H1:
H0: genetic independence θ = 1/2 and Hl: linkage of θ1
0 ≤ θ1 < ½.
The lod score of the θ1 sample Z(θ1) = log10
[L(θ1)/L(l/2)] indicates the relative probabilities of
finding that the sample is Hl or H0. Thus, a lod score of
3 means that the probability of finding that the sample
is Hl is 1000 times greater than of finding that it is H0
("lod = logarithm of the odds").
The decision thresholds of the test are usually set at -2
and +3, so that if:
Z(θ1) 3 H0 is rejected, and linkage is accepted.
Z(θ1) ≤ -2 linkage of θ1 is rejected.
-2 < Z(θ1) < 3 it is impossible to decide between H0
and Hl. It is necessary to go on accumulating
information.
For the thresholds chosen, -2 and +3, we can show that:
The first degree error, α < 10-3
The second degreee error, β < 10-2
The reliability, 1-ρ > 0.95 ∀ θ1
The power, P(θ) > 0.80 ∀ θ1 if the true value of θ <
0.10
I- 2. Definition of the "lod score" of a
family
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Figure 7
325
Genetic Linkage Analysis
Clerget-Darpoux F
Details about the principle underlying the test are to be
found in Wald (2), and the justification for criteria -2
and +3 in Morton (1).
In fact, what is being tested is not a single value of θ1
relative to θ = 1/2, but a whole set of values between 0
and 1/2, with a step of various size (0.01 or 0.05). If
there is a value of θ1 such that Z(θ1) = 3: linkage is
concluded to exist.
Figure 10
The proposed test has the advantage of being very
simple, and of providing protection against falsely
concluding linkage. However, some criticisms can be
levelled, not only against the criteria chosen (Chotai
(3)), but also against the entire principle of using a
sequential procedure (Smith (4)). The number of
families typed is, indeed, rarely chosen in the light of
the test results.
Figure 8
If there is a value of θ1 such that Z(θ1) = -2
The linkage is excluded for any θ ≤ θ1
If ∀ θ -2 < Z(θ) < 3, no conclusion can be drawn, the
sample is not sufficiently informative.
Figure 9
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
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Genetic Linkage Analysis
Clerget-Darpoux F
configuration, weighting it by the probability of this
configuration, and knowing the phenotypes of
individuals in A and B.
Knowledge of the genetic parameters at each of the loci
(gene frequency, penetration values) is therefore
necessary before we can estimate θ (Clerget-Darpoux
et al (5)). It is obvious that calculating the lod scores,
despite being simple in theory, is in fact a lengthy and
tedious business. In 1955, Morton provided a set of
tables giving the lod scores for various values of θ for a
disease locus and a marker locus for nuclear families
with sibling sizes of 2 to 7. However, the situations
envisaged were very restrictive. In particular, it was
assumed that the disease was determined by a dominant
or recessive completely pentrating rare gene.
"LIPED" written by Ott in 1974 (6) was the pioneering
software in linkage analysis. It is able to carry out this
calculation, in an extensive pedigree for any values of
q, f1, f2, f3 and for penetration as a function of age. The
"Linkage" program of Lathrop et al, 1984 (7,8) is the
one most often used for gene mapping. It can be used to
carry out multipoint analysis.
All the software we have described is based on the
same recursive algorithm, r (Elston and Stewart), which
means that it can be used to investigate pedigrees of
any size, but that it envisages all the possible
haplotypical combinations of markers, and is therefore
limited by the number of markers to be taken into
account. In contrast, "Genehunter" (9), which is based
on a Markov chain principle, is limited not by the
number of markers taken into consideration in the
analysis, but by the size of the family structure. The
very recently developed software package "Allegro"
(10) can apply information from a large number of
markers and extended family structures.
Analysis of gene linkage has made it possible to
construct a gene map by locating the new
polymorphisms relative to one other on the genome.
The measurement used on the gene map is not the
recombination fraction, which is not an additive datum,
but the gene distance, which we will define below.
I- 4. Estimation of the recombination
fraction
If the test, on a sample of the family, has demonstrated
linkage between the A and B loci, then one may want
to estimate the recombination fraction for these loci.
The estimated value of θ is the value which maximizes
the function of the lod score Z, and this is equivalent to
taking the value of θ for which the probability of
observing linkage in the sample is greatest.
I- 5. Recombination fraction for a disease
locus and a marker locus
Let us assume we are dealing with a disease carried by
a single gene, determined by an allele, g0, located at a
locus G (g0: harmful allele, G0: normal allele). We
would like to be able to situate locus G relative to a
marker locus T, which is known to occupy a given
locus on the genome. To do this, we can use families
with one or several individuals affected and in which
the genotype of each member of the family is known
with regard to the marker T. In order to be able to use
the lod scores method described above, what is needed
Figure 11
is to be able to extrapolate from the phenotype of the
individuals (affected, not affected) to their genotype at
locus G (or their genotypical probability at locus G).
What we need to know is:
1. the frequency, g0
2. the penetration vector f1, f2,f3
f1 = proba (affected /g0g0)
f2 = proba (affected /g0G0)
f3 = proba (affected /G0G0)
It will often happen that the information available for
the marker is not also genotypic, but phenotypic in
nature. Once again, all possible genotypes must be
envisaged.
As a general rule, the information available about a
family concerns the phenotype. To calculate
thelikelihood of θ, we must envisage all the possible
genotype configurations at each of the loci, for this
family, writing the likelihood of θ for each
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
I- 6. Linkage analysis for three loci : the
phenomenon of interference
(V. Bailey, 1961)
Now let us consider three loci A, B and C. Let the
recombination fraction between A and B be θ1, that
between B and C be θ2 and that between A and C be θ3.
Figure 12
327
Genetic Linkage Analysis
Clerget-Darpoux F
Let us consider the double recombinant event, firstly
between A and B, and secondly between B and C. Let
Rl2 be the probability of this event. If the crossings-over
occur independently in segments AB and BC, then:
Rl2 = θ1θ2
If this is not the case, an interference phenomenon is
occurring and Rl2 = C θ1 θ2 where C 1
If C < 1 the interference is said to be positive; and
crossings-over in segment AB inhibit those in segment
BC.
If C >1 the interference is said to be negative; and
crossings-over in segment AB promote those in
segment BC.
Let us consider the case of a triple heterozygotic
individual.
Such an individual can provide 8 types of gametes.
x(θ) = -1/2 Log (1-2θ) is an additive measurement.
It is known as the genetic distance, and is measured in
Morgans. It can be shown that x measures the mean
number of crossings-over.
Test for the presence of interference
Let us consider a sample of families with the genotypes
A, B and C. Let Lc be the greatest likelihood for θ1, θ2,
θ3 and L1 the greatest likelihood when we impose the
constraint C=1 (i.e. θ3 = θ1 + θ2 - 2θ1θ2)
Then -2 Log (Ll/Lc ) follows a χ2 pattern, with one
degree of freedom.
I- 7. References
Figure 13
Figure 14
1.
Morton NE. Sequential tests for detection of linkage. Am J
Hum Genet 1955; 7: 277-318.
2.
Wald A. Sequential analysis. New York: Wiley,1977.
3.
Chotai J. On the lod score method in linkage analysis.
Ann Hum Genet 1984; 48: 359-378.
4.
Smith CAB. Some comments on the statistical methods
used in linkage investigations. Am J Hum Genet 1959; 11:
289-304.
5.
Clerget-Darpoux F.; Bonaïti-Pellié C, Hochez J. Effects of
mispecifying genetic parameters in lod score analysis.
Biometrics 1986; 42: 393-399.
6.
Ott, J. Estimation of the recombination fraction in human
pedigrees: Efficient computation of the likelihood for
human linkage studies. Am J Hum. Genet 1974; 36: 363386.
7.
Lathrop GM, Lalouel, J. Easy calculations of lod scores
and genetic risks on small computers. Am J Hum Genet
1984; 36(2): 460-465
8.
Lathrop GM; Lalouel JM; Julier C; Ott J. Multilocus linkage
analysis in humans. Detection of linkage and estimation of
recombination. Am J Hum Genet 1985; 37: 482-498.
9.
Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES.
Parametric and Nonparametric Linkage Analysis: A
Unified Multipoint Approach. Am J Hum Genet 1996; 58:
1347-1363.
10. Gudbjartsson DF, Jonasson K, Frigge M, Kong A. Allegro,
a new computer program for multipoint linkage analysis.
Nature Genet 2000; 25: 12-13
11. Bailey N. Introduction to the mathematical theory of
genetic linkage. London: Oxford University Press, Amen
House,1961.
12. Ott, J. Analysis of human genetic linkage. Johns Hopkins
University Press, 1985.
13. Morton NE. The detection and estimation of linkage
between the genes for elliptocytosis and the Rh blood
type. Am J Hum 1956; 8: 80-96.
14. Smith CAB. Testing for heterogeneity of recombination
fractions in human genetics. Ann Hum Genet 1963; 27:
175-182.
Figure 15
We can write that
θ3 = θ1 + θ2 -2 R12
θ3 = θ1 + θ2 -2 Cθl θ2
If C = 1 θ3 = θ1 + θ2- 2θ1θ2
The recombination fraction is a non-additive
measurement. However, we can write
(1-2θ3) = (1-2θ1)(1-2θ2)
if x(θ) = k Log (1-2θ)
then we have x(θ3) = x(θ1) + x(θ2)
and for k = -1/2, x(θ)∼θ for small values of θ.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
IIGenetic
localization
heterogeneity
of
The analysis of genetic linkage can be complicated by
the fact that mutations of several genes, located at
different places on the genome, can give rise to the
same disorder. This is known as genetic heterogeneity
of localization. One of the following two tests is used
to identify heterogeneity of this type, the "Predivided
328
Genetic Linkage Analysis
Clerget-Darpoux F
sample test" or the "Admixture Test". The first test is
usually only appropriate if there is a good family
stratification criterion or if each family individually has
high informativity.
II- 3. Generalization of the "admixture
test"
In some single-gene diseases, several genes have been
shown to exist at different locations. This is true, for
example of multiple exostosis disease, for which 3
genes have been identified successively on 3 different
chromosomes. The "admixture test" is then extended to
determine the proportion of families in which each of
the three genes is implicated (Legeai-Mallet et al,
1997), and the possibility that there is a fourth gene.
The three locations on chromosomes 8, 19 and 11 were
reported as El, E2 and E3, and the proportions of
families concerned as αl, α2 and α3 respectively. α4 was
used to represent the proportion of the families in
which another location was involved.
For each family i of the sample, the likelihood was
calculated using the observed segregation within the
family of the markers available in each of the three
regions, according to the clinical status of each of its
members.
Li(El, E2, E3,αl, α2, α3/Fi) = αl (L(E1/Fi)/L(El=1/2/Fi)]
+ αl(L(E2/Fi)/L(E2=1/2/Fi)] + α3 [L(E3/Fi)/L(E3=1/2/
Fi)]+ α4.
For all the families
L(El, E2, E3,αl, α2, α3/ ΠFt) = i Li(El, E2, E3,αl, α2, α3
/ Fi)
Each αi can be tested to see if it is equal to 0, and then
the corresponding non nullα i and Ei values are
estimated.
It is also possible to calculate the probability that the
gene implicated is at El, E2 or E3 for each of the
families in the sample. The post hoc probability makes
use of the estimated αi proportions, but also the specific
observations in this family.
The sample investigated has been shown to consist of
three types of families: in 48% of families, the gene is
located on chromosome 8, in 24% of them on
chromosome 19, and in 28% of families the gene is
located on chromosome 11. There was no evidence of a
fourth location in this sample. The post hoc
probabilities of belonging to one of these 3 sub-groups
were then estimated: the probability that the gene
implicated would be on chromosome 8 was over 90%
for 5 families, that it would be on chromosome 19 for 3
of them, and that it would be on chromosome 11 for 4
families. For the other families, the situation was less
clear-cut: the post-hoc probabilities are similar to the
ad hoc probabilities because of the paucity of
information provided by the markers used.
II- 1. The "Predivided sample test"
This test is intended to demonstrate linkage
heterogeneity in different sub-groups of a sample of
families. The aim is to test whether the genetic linkage
between a disease and its marker(s) is the same in all
sub-groups. These groups are formed ad hoc on the
basis of clinical or geographical criteria etc....
Let us assume that the total sample of families has been
divided into n sub-groups (it is possible to test for the
existence of as many sub-groups as families). θi denotes
the true value of the recombination fraction of subgroup i. We want to test the null hypothesis H0: θ1=
θ2= θ3= …= θn against the alternative hypothesis Hl:
the values of θi are not all equal. Therefore, the
quantity
Figure 16
follows a χ distribution2 with (n-l) degrees of freedom.
The homogeneity of the sample for linkage with a typeI error of the sample for linkage with a type I error
equal to α if Q is above the critical threshold χ2(n-l)
corresponding to α.
II- 2. The "Admixture Test"
Unlike the previous test, the "admixture test" is not
based on an ad hoc subdivision of the families. It is
assumed that among all the families studied genetic
linkage between the disease and the marker is found
only in a proportion α of the families, with a
recombination fraction θ < 1/2. In the remaining (l-α)
families, it is assumed that there is no linkage with the
marker (θ=1/2).
For each family i of the sample, the likelihood is
calculated
Li(α, θ) = α Li(θ) + (l-α) Li(1/2), where Li(θ) is the
likelihood of θ for family i. The likelihood of the
couple, (α, θ) is defined by the product of the
likelihoods associated with all the families: L(α,θ)= Πi
Li(α,θ).
We test to find out whether α is significantly different
from 1 by comparing Lmax(α = l,θ), the maximized
likelihood for θ assuming homogeneity, and Lmax(α,θ),
the maximized likelihood for the two parameters α and
θ (nested models).
Then variable Q =2[Ln Lmax (α,θ) —Ln Lmax (α= 1,θ)],
follows a χ2 distribution with one degree of freedom.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
II- 4. References
1.
329
Legeai-Mallet L, Margaritte-Jeannin P, Clerget-Darpoux F
et al. Genetic heterogeneity of hereditary multiple
exostoses. Hum Genet 1997; 99: 298-302.
Genetic Linkage Analysis
Clerget-Darpoux F
2.
Morton N. The detection and estimation of linkage
between the genes for elliptocytosis and the Rh blood
type. Am J Hum Genet 1956; 8: 80-96.
3.
Smith CAB. Testing for heterogeneity of recombination
values in human genetics. Ann Hum Genet 1963; 27: 175182.
III- Statistical properties
method of lod scores
of
The conditions of application which underlie these
properties: sequentiality, segregation of a simple
single-gene disease in nuclear families, in which all the
members are genotyped for a genetic marker, and the
non-ambiguity of the test is not confirmed in practice.
The table below shows the change in these conditions
of application. We discuss here the impact of these
changes on the statistical properties.
the
III- 1. The test procedure
The test procedure used in the method of lod scores is
sequential (Wald, 1947). The amount of information,
i.e. the number of families is accumulated in the
sample, until it is possible to decide between the H0
and H1 hypotheses:
H0: genetic independence θ = ½ and
H1: linkage to θ1, 0 ≤ θ1 < 1/2
The value of the lod score of the sample in θ1
z(θ1) = log10 [L(θ1)/L(1/2)] indicates the relative
probabilities of observing the sample as H1 or H0.
Thus, a lod score of 3 implies that the probability is
1000 times greater of observing the sample as H1
rather than H0 ("lod=logarithm of the odds").
The decision thresholds of the test are usually set at -2
and +3, so that if:
Z(θ1) 3 H0 is rejected and linkage is concluded
Z(θ1)≤ 2 linkage is rejected for θ1.
-2 < Z(θ1) < 3 it is impossible to decide between H0
and H1.
It is necessary to go on accumulating information.
For the -2 and +3 thresholds selected, it can be shown
that:
The first degree error α < 10-3
The second degree error β < 10-2
The reliability 1-ρ > 0.95 ∀θ1
The power P(θ) > 0.80 ∀θ1 if the true value of θ < 0.10
III- 1.1. Impact of non-sequentiality
In general, one is working on a sample of families of a
fixed size. This problem of non-sequentiality was
raised by Smith (1959) and investigated by Chotai
(1984) and Guihenneuc (1991), who have shown that
the type-1 error of the test was not increased, but on the
contrary reduced.
Furthermore, the power will obviously depend on the
size the sample. It also depends on the parameters of
the genetic model (penetrations, frequency of the
morbid allele, degree of dominance), of the types of
family analysed (nuclear or extensive families), the
informativity of the markers, of what is known about
the phase of the alleles at the disease locus and the
marker locus, and of the value of the recombination
fraction between these two loci.
If one knows all about the genetic model of the
transmission of the disease and its parameters, the
greater the power of the method, the easier it is to
detect the presence of recombination between the
disease locus and a marker locus, in other words, the
genotype of each of the two loci, but also the
haplotype, i.e. the combination of 2 alleles from each
locus on the same chromosome segment are easily
identifiable from the phenotype. At the disease locus,
the genotype can be deduced unambiguously from the
phenotype if there is a rare dominant gene with total
penetrance for the heterozygote and zero penetrance for
the normal homozygote (no phenocopy). The power
diminishes as the degree of dominance and the
penetrance decline, and the gene frequency and
proportion of phenocopies increase (Ott, 1991).
Figure 17
Figure 18
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
330
Genetic Linkage Analysis
Clerget-Darpoux F
At the marker locus, this power is greater the higher the
degree of heterozygotism, or in other words, the more
polymorphic the marker. If we consider the two loci
together, the amount of knowledge about the haplotype
transmitted is greater if there are a large number of
generations. Finally, the proximity of the two loci
increases the power of detection of the genetic linkage.
Multipoint linkage analysis, which uses several
reference markers near to each other on a given
chromosome segment, increases the power of the
method by increasing the informativity of the meioses.
In general, it is used to pinpoint the location of a
morbid locus once it has been established that genetic
linkage is present.
III- 1.2. Maximization of the lod score over the [0,
1/2] interval
(Ref: Génin E., Ann Hum Genet,1995,59:123-132)
However, in practice, the test is never carried out for a
single value of θ1, but is done as follows: the lod score
is calculated for various values of θ1, the maximum lod
score Zmax is calculated and the test is applied to Zmax
.A criterion of +3 or even less, is used to conclude that
linkage is occurring, based on the argument that risk
remains sufficiently small. The probability of the posthoc non linkage is never calculated.
The fact of considering an alternative hypothesis by
using the maximum lod score, Zmax (which amounts to
testing H0: θ = 1/2 versus H1: θ < 1/2) actually reduces
the reliability of the test considerably. Thus, the
probability ρ that there is no linkage when a Zmax of + 3
has been obtained can be as high as 16.4%; i.e. more
than three times the probability calculated by Morton
(1955).
for a dominant disease in a sample of nuclear families
with two children). Reliability =1-ρ.
The example of the conflicting results obtained for
Alzheimer’s disease is a good illustration of the
usefulness of calculating the probability of linkage post
hoc. Alzheimer’s disease is a form of dementia
characterized by loss of memory and of cognitive
function. Only a few families have multiple cases, but
within this sub-group of families, the distribution of the
patients is compatible with the hypothesis of the
intervention of a dominant mutation on an autosomal
gene. Analyses of genetic linkage by the method of lod
scores were therefore carried out to localize the gene
involved. In 1987, a maximum lod score of +2.46 was
obtained using a marker of chromosome 21 in a large
genealogy with numerous members affected (family
FAD4), and this at first led people to conclude that the
mutation responsible was located on chromosome 21
(St Georges-Hyslop et coll. 1987). For many years,
research into this disease was therefore focused on this
chromosome. Five years later however, several
different teams provided a very significant
demonstration of linkage with chromosome 14
markers. The very high lod scores that were obtained
showed that most of the early familial forms were due
to a mutation of a chromosome 14 gene 14
(Schellenberg et coll. 1992, St Georges-Hyslop et coll.
1992). In particular, in the case of family FAD4, a lod
score of +5.21 was obtained with markers for this
region. In view of the observations obtained for
chromosome 21 markers in FAD4, the post-hoc
probability that there was no linkage was 1/3. It is
likely that if this calculation had been done in 1987, the
existence of a mutation on chromosome 21 in this
family would have looked less convincing.
Furthermore, it has now been shown that the gene
implicated is located on chromosome 14.
III- 1.3 References
The table below shows the probability that linkage does
not exist as a function of the Zmax obtained.
1.
2.
3.
4.
Génin E, Martinez M, Clerget-Darpoux F. Posterior
probability of linkage and maximal lod score. Ann Hum
Genet 1995; 59: 123-132.
Schellenberg GD, Bird T, Wijsman E et al. Genetic
linkage evidence for a Familial Alzheimer's disease locus
on chromosome 14. Science 1992; 258: 668-671.
St Georges-Hyslop PH, Haines J, Rogaev E et al. Genetic
evidence for a novel familial Alzheimer's disease locus on
chromosome 14. Nature Genet 1992; 2: 330-334.
St Georges-Hyslop PH, Tanzi RE, Polinsky RJ et al. The
genelic defect causing Alzheimer's disease maps on
chromosome 21. Science 1987; 235: 885-890.
III-2. Genotype information
III-2.1.
Ambiguity
in
phenotype-genotype
relationships at the disease locus
The original lod score method was applied to the study
of nuclear families (the parents and their children), and
this made it easy to deduce the genotype at each of the
loci for each member of the family. Since it is the
Figure 19
The relationship between ρ and Zmax depends on the
type of family structure and the determinism of the
disease (in this case the calculation has been carried out
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
331
Genetic Linkage Analysis
Clerget-Darpoux F
are linked by the constraint of the value of the
prevalence of the disease within the population.
III-2.2. Ambiguity in the marker genotype
To calculate a lod score between a disease locus and a
marker locus, it is necessary to take into consideration
all the possible genotypical configurations at each of
the loci and to write the probabilities of these
configurations. If some individuals have not been
genotyped for the genetic marker, the probability of
each possible genotype must be calculated. To do this,
is will be necessary to specify the allele frequencies of
the marker.
Any error in thee allele frequencies, in particular the
under-estimation of the frequency of an allele in the
patients, artificially increases the values of the lod
score and can therefore lead to a false conclusion that
there is genetic linkage (false positives) (Ott, 1991 ;
Freimer et al, 1993; Knapp et al, 1993).
In increasingly frequent use of very extensive
genealogies, in which only individuals of the last
generation are typed, alls for great caution in
interpreting positive results.
III-2.3. Gamete disequilibrium between alleles at the
disease locus and at the marker locus
An association between a susceptibility gene and a
marker can lead to bias in the estimation of the
recombination fraction. In particular, the "lod scores"
method specifies that there must be no selection for the
marker in the sample. However, in a context of an
association, selection based on the status of the patient
implicitly involves selection for a marker. Furthermore,
the calculation assumes that the probability for each
genetic combination is equal in the parents, and this is
not true if there is an association. In the analysis, failing
to take into account the disequilibrium existing
between disease alleles and marker alleles, induces a
very great under-estimation of the "lod score" (in other
terms, a marked reduction in the power of the linkage
test) and a very slight under-estimation of the
recombination fraction (Clerget-Darpoux, 1982).
phenotypes that can be observed this means that the
phenotype/genotype correspondence was known. In
particular, when the analysis was carried out between a
"disease" locus and a "marker" locus, the disease was
assumed to involve a single gene, due to a rare allele of
an autosomal gene, or linked to gender, with complete
penetrance (probability of being affected equal to 1 for
people carrying one copy of the allele for dominant
diseases, of two copies for recessive diseases). Gamete
equilibrium was also assumed to exist between the
alleles at the "disease" locus and the "marker" locus.
The method, the properties of which were fully
established on the basis of these hypotheses, has been
extended over the past twenty years to more varies and
complex situations, but without questioning its
underlying properties. In particular, it is applied to
diseases of which the determinism is less or even
totally unknown, which are studies in large
genealogies, of which some of the members have an
unknown phenotype. This leads us to investigate the
power of the test using various models and its
robustness to modeling errors.
It should be stressed that the "lod score", which is
thought of above all as a function of the recombination
fraction and used to estimate this variable, also depends
on the value of the genetic parameters at the disease
locus, i.e. the frequency of the alleles at this locus and
the penetrances (probabilities of being affected)
associated with each of these genotypes.
We evaluated the effects that an error in these
parameters produced in the linkage test and in
estimating the recombination fraction (Clerget-Darpoux
et coll, 1986,1992,1993).
- Loss of power: The power of detecting linkage can
be very severely reduced if there is an error
concerning the relative penetrance of each of the
genotypes: i.e. concerning the ratio of probabilities
of being affect in those who carry two copies of the
morbid allele, those who have a single copy and
those who do not carry it at all, "the phenocopies".
- False exclusion of linkage: The robustness of the
method to false specifications of the values of the
parameters is not symmetrical with regard to the two
hypotheses being tested. We have shown that the lod
score is always, greatest for the correct values of the
parameters and that it can be considerably reduced if
these have been wrongly specified. As a
consequence, an error in the values of the parameters
does not lead to a false conclusion of linkage
although it can wrongly lead to the exclusion of
linkage. This is particularly the case if the proportion
of phenocopies is underestimated.
- Bias in the recombination fraction: The estimation
of the recombination fraction is very sensitive to any
error in the value of any of the parameters. In
addition, the effects of the errors on the gene
frequency and on the penetrance values are usually
additive, because in most studies these parameters
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
III-3. The problem of multiple tests
One of the difficulties encountered in the statistical
interpretation of the analyses of the genetic linkage of
complex diseases arises in fact from the fact that in
general and with a varying degree of explicitness, the
data are subjected to multiple tests: several clinical
classifications, several genetic markers, several models,
several samples. It is quite clear that the
discontinuation criteria usually used in the lod score
test no longer have the same statistical significance
when several tests are applied simultaneously to the
same sample or to several samples. E. Thompson
(1984) has investigated this problem in the case of a
disease involving a single gene for which the genetic
linkage is tested using several markers located on
different chromosomes (and therefore independent).
332
Genetic Linkage Analysis
Clerget-Darpoux F
The situation is much more complex for multifactorial
diseases, because the multiplicity of the tests has
several types of impact and these are not independent
(Clerget-Darpoux et coll, 1990). Multiple tests could be
taken into account by readjusting the discontinuation
criterion of the lod scores test. However, on the one
hand, it is not always clear from the publications which
tests have actually been carried out, and on the other,
this can make the test too conservative. This is why we
think that the replication strategy should be favored.
If a positive result is replicated for a new sample (using
the same classification, the same marker, the same
transmission model) this provides a reliable threshold
of significance.
III-4. References
4.
Clerget-Darpoux F, Babron M.C., Bonaïti-Pellié C.
Assessing the effect of multiple linkage tests in complex
diseases. Genet Epidemiol 1990; 7: 245-253.
5.
Clerget-Darpoux F, Bonaïti-Pellié C. Strategies based on
marker information for the study of human diseases. Ann
Hum Genet 1992; 56: 145-153.
6.
Clerget-Darpoux F, Bonaïti-Pellié C. An exclusion map
covering the whole genome: a new challenge for genetic
epidemiologists ? Am J Hum Genet 1993; 52: 442-443
7.
Freimer NB, Sandkuijl LA, Blower SM. Incorrect
specification of marker allele frequencies : effect on
linkage analysis. Am J Hum Genet 1993; 56: 1102-1110.
8.
Guihenneuc C, Prum B, Clerget-Darpoux F, Bonaïti-Pellié
C. Remarques sur la méthode du lod score en génétique.
Pub Inst Stat Univ Paris 1990; 35: 19-37.
9.
Knapp M, Seuchter SA, Bauer MP. The effect of
misspccifying allele frequencies in incompletely typed
families. Genet Epidemiol 1993; 10: 413-418.
1.
Chotai J. On the lod score method in linkage analysis.
Ann Hum Genet 1984; 48: 359-378.
10. Morton NE. Sequential tests for the detection of linkage.
Am J Hum Genet 1955; 7: 277-318.
2.
Clerget-Darpoux F. Bias of the estimated recombination
fraction and lod score due to an association beween a
disease gene and a marker gene. Ann Hum Genet 1982;
46: 363-372.
11. Ott J. Analysis of human genetic linkage, 2nd ed ition.
John Hopkins University Press, 1991.
3.
12. Smith CAB. Some comments on the statistical methods
used in linkage investigations. Am J Hum Genet 1959; 11:
289-304.
Clerget-Darpoux F, Bonaïti-Pellié C, Hochez J. Effects of
misspecifying genetic parameters in 1od score analysis.
Biometrics 1986; 42: 393-399.
13. Wald A. Sequential analysis. New York: Wiley, 1947
This article should be referenced as such:
Clerget-Darpoux F. Genetic Linkage Analysis. Atlas Genet
Cytogenet Oncol Haematol. 2002; 6(4):323-333.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
333
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Educational Items Section
Consanguinity
Robert Kalmes, Jean-Loup Huret
Institut de Recherche sur la Biologie de l'Insecte, IRBI - CNRS - ESA 6035, Av. Monge, F-37200 Tours,
France (RK); Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers
Hospital, F-86021 Poitiers, France (JLH)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Educ/ConsangID30039ES.html
DOI: 10.4267/2042/37916
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
I- Definition
II- Coefficient of consanguinity of an individual
II- 1.Formulation
II- 2.General formula
III- Consanguinity of a population
IV- Self-fertilization
V- Generalization
V- 1. Genotype frequencies at equilibrium
V- 2. Properties of consanguinity
VI- Human population
VII- Genetic counselling
VIII- Rare alleles - Common alleles
VIII-1. Exercice
VIII-2. Practical consequences
IX- Consanguinity - Heterozygotism - Isogenetic line
X- Multiallele system
X- 1 Exercice: Consanguinity for a locus and three alleles
I- Definition
II- Coefficient of consanguinity of
an individual
A subject is in a situation of consanguinity if, for a
given locus, (s)he has two identical alleles, per copy of
one and the same ancestor gene.
The coefficient of consanguinity (Cc or F) is the
probability that the two allele genes that an individual
has at a locus are identical by descendance.
→ This assumes that a common ancestor (A) is shared
by the parents, F and M, of the individual, I studied.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
II- 1.Formulation
First, look for the common ancestor (or common
ancestors) on the genealogical tree.
Then, calculate the probabilities; for example:
334
Consanguinity
Kalmes R, Huret JL
value of F = 1/16, and 1.5% a value of F = 1/32; what
is the consanguinity of this population?
Answer: α= (2.5 X 1/8) + (2 X 1/16) + (1.5 X 1/32) =
0.484%
IV- Self-fertilization
This means that each genotype is fertilized exclusively
by itself (a situation that is possible in maize (corn), but
not in Drosophila, or in Man).
In a population of plants, underHW in Go, which is
then put in a situation of self-fertilization:
Figure 1
A possesses alleles a1 and a2. It transmits to the greatgrandparents GGP:
• either identical alleles (a1 and a1 or: a2 and a2) →
proba: 1/2
• or different alleles (a1 and a2 or: a2 et a1),
but... if A itself exhibits consanguinity (with a
coefficient of consanguinity FA), then a1 and a2 have a
probability FA of being identical, and A transmits a1
and a2 with a proba 1/2, i.e. FA x 1/2
Overall, A transmits the identity with a proba: 1/2 + 1/2
FA, or: 1/2 (1 + FA) Note: FA can be equal to zero.
Each generation i has a proba 1/2 of transmitting this
allele to i+1; therefore a proba (1/2)n after n
generations; or (1/2)p to go from GGP1 to I and (1/2)m
to go from GGP2 to I, if f and m are the number of
links linking the father and mother respectively to the
common ancestor (here p = m = 3).
Therefore: FI = (1/2)p+m+1(1+FA) ...
And, if there are several common ancestors (not
consanguinous with each other), a sum Σ, addition of
the various consanguinities, gives us the:
AA
Aa
aa
Go
0.25
0.50
0.25
self-fertilization
AA
X 1 X1/4
G1
Aa
aa
aa
X1/2 X1/4
0.25 0.125 0.25
AA
Aa
X1
0.125 0.25
aa
etc...
What is the frequency Hn of the heterozygotes in
generation n?
Hn = 1/2 Hn-1 → Hn = (1/2)nHo; tends
towards zero.
Dn = Dn-1 + 1/4 Hn-1
Rn = Rn-1 + 1/4 Hn-1
→ at the equilibrium of self-fertilization: Deq = Do +
1/2 Ho; Heq = 0; Req = Ro + 1/2 Ho
Being under HW in Go, Do = p2; Ho = 2pq; Ro = q2
→ Deq = p2 + 1/2 2pq = p2 + pq = p (p +q) = p;
similarly for Req →
II- 2.General formula
Genotype frequencies at equilibrium:
Deq = p
Heq = 0
Req = q
FI = Σ(1/2)p+m+1(1+FAi)
Note: FA is negligible in man and at the level of the
individual, but may not be in Drosophila, particularly in
an entire population.
Genealogy studies are indispensable for determing
consanguinity; see: Genealogy and Coefficient of
Consanguinity, Exercices.
V- Generalization
Genotype
III- Consanguinity of a population
The mean coefficient of consanguinity is equal to the
mean of the various individual coefficients weighted by
the frequencies of the various types of crosses between
related individuals.
To evaluate this, an inventory is compiled for the
individuals of the different types of crossings between
related individuals, and they are classified on the basis
of the value of Fx.
EQUATION
α = Σ Fifi where fi is the frequency of the subjects with
consanguinity Fi.
Example: a population in which 6% are consanguin,
and among these: 2.5% have a value of F = 1/8; 2% a
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
AA
AA
Aa
aa
General case
panmixia
selffertilization
0 <= F <= 1
F=0
F=1
allozygotism +
autozygotism
p2(1-F) + pF
2pq(1-F)
q2(1-F) + qF
p2
2pq
q2
p
0
q
Thus, any population (and this includes a consanguin
population) will behave as though:
• one fraction (1-F) was developing in panmixia
• one fraction F was developing in self-fertilization
F being the mean coefficient of consanguinity of the
population. F=0 in panmixia, F=1 in self-fertilization.
The genotype frequencies at equilibrium will be:
335
Consanguinity
Kalmes R, Huret JL
F(AA)eq = p2(1 - F) + pF = p2 - p2F + pF = p2 + Fp (1
- p) = p2 + Fpq; similarly for F(aa); thus:
Note: the exact equation q2+ pqCc is replaced by the
approximation: q x Cc. This is applicable to human
genetics (genetic counselling) if/because q is very
small.
V- 1. Genotype frequencies at equilibrium
EQUATION:
F(AA)eq = p2 + Fpq
F(Aa)eq = 2pq(1 - F)
F(aa)eq = q2 + Fpq
Exercice 1: Parents first cousins; for a mutant gene
with recessive autosomal transmission with frequency q
= 1/100 (example of phenylketonuria, one of the most
common recessive autosomal diseases): what is the risk
in the general population? What is the risk that I could
be affected?
Answer:
For the general population: q 2 = 1/10 000
For I, it is, according to the equation: q x Cc = 1/100 x
1/16 = 1/1 600
Note: the risk of a recessive autosomal disease in the
individual I, relative to the general population, is
increased by the factor: q x Cc / q 2 = Cc / q here = 6.25
(or, if we use the accurate equation (q2+ pqCc) / q 2 =
7.19)
EQUATION:
The risk that a consanguin subject will be homozygotic
for the allele a is: F(aa) = q2 + Fpq
Another demonstration of the relations F(AA) = p2 +
Fpq, F(Aa) = 2pq(1 - F), et F(aa) = q2 + Fpq is given in:
Genetic Constitution of Consanguin Populations.
Are the allele frequencies altered?
F(A) = D + H/2 = p2 + Fpq + 2pq(1 - F)/2 = p2 + Fpq +
pq - Fpq = p2 + pq = p(p + q) = p → invariable;
therefore:
V- 2. Properties of consanguinity
Exercice 2: same exercice, but for a frequency q = 1/10
000 of the mutant gene.br
Answer:
For the general population: q 2 = 1/100 000 000
For I, it is, according to the equation: q x Cc = 1/10
000 x 1/16 = 1/160 000
The risk for individual I relative to the general
population, is increased by a factor Cc / q here = 625
or, if we use the accurate equation, q2+ pqCc / q 2 = 626
(the rarer the allele, the better the approximation q x
Cc).
Consanguinity:
• modifies the genotype frequencies. We can see an
increase in the frequency of homozygotes and a
reduction in that of heterozygotes.
• does not modify the allele frequencies
VI- Human population
It is usual within the human population for there to be
several common ancestors (e.g. below: AM and AF
male and female ancestors, parents of GP 1 and 2). In
practice, the equation is simplified to:
EQUATION
CcI = Σ(1/2)p+m+1
Example: Parents first cousins: p=2; m=2; Σ is the sum
of 2 terms, since there are 2 possibilities of having
identical alleles: via AM and via AF (i.e. 2 common
ancestors); so,
Answer: Fi = (1/2)2+2+1 + (1/2)2+2+1 = 1/16
VIII- Rare alleles-Common alleles
VIII-1. Exercice
Consider a gene A of which the recessive allele a has a
freqency F(a) = q = 0.5 and a gene B of which the
recessive allele b has a freqency F(b) = q = 0.0001, a
fairly usual frequency for a morbid allele, calculate the
frequency/risk of being recessive homozygote(s) for
each of these two genes
1. according to Hardy-Weinberg (HW)
2. for a consanguin child whose parents are firstcousins
3. compare
Answer:
1. According to HW:
• F(aa) = q2 = (0.5)2 = 0.25
• F(bb) = q2 = (0.0001)2 = (10-4)2 = 10-8
2. for a consanguin child whose parents are firstcousins:
• Σ(1/2)p+m+1= (1/2)5 + (1/2)5 = (1/2)4 = 0.0625
• F(aa) = q2 + Fpq = (0.5)2 + 0.0625 X 0.5 X 0.5 =
0.2656
Figure 2
VII- Genetic counselling
For a deleterious mutant recessive autosomal allele
(rare by definition) with a frequency q, the risk that a
consanguin child will be homozygotic for this allele is:
q x Cc whereas it is q2 for the children of nonconsanguin parents.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
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Consanguinity
Kalmes R, Huret JL
• F(bb) = q2 + Fpq = (10-4)2 + 0.0625 X 1 X 10-4 = (1
+ 625)10-8 = 626 X 10-8
3. comparison: the increase in the frequency (risk) of
homozygotism due to the consanguinity will be
F(consang.)/F(under HW), i.e.:
• for the common allele: 0.26256 / 0.25 = 1.06,
slight increase
• for the rare morbid allele: 626 X 10-8/10-8 = 626 !!!
A sample of 400 individuals is examined. The numbers
of the various genotypes are as follows.
A1A1
32
1.
2.
VIII-2. Practical consequences
4.
A2A2
57
A2A3
90
A3A3
125
Answer:
1. The allele frequencies are estimated by counting
the alleles. Thus, for allele A1 for example:
frequency of A1 = ((2 x 32) + 36 + 60) / (2 x 400)
= 0.20 = p
similarly: frequency of A2= 0.30 = q; frequency of
A3 = 0.50 = r
2. The proportions of panmixia are in fact those
indicated by the Hardy-Weinberg law.
a. Theoretical frequencies of the genotypes
according to the Hardy-Weinberg law
IX- Consanguinity - Heterozygotism Isogenetic line
In the human species, the percentage of heterozygotic
loci, calculated from enzymatic polymorphism, has a
value H = 0.067. We can take it that there are 30000
structural genes and in consequence 2010 genes in the
heterozygotic state in the human genome (30000 x
0.067 = 2010).
If an individual results from an uncle-niece cross:
this individual will be more "homogenous" than his or
her parents, because of the increased consanguinity, the
percentage of his/her hetero-zygotic genes falls from
2010 to 1759 genes (2010 x 7/8) since Fi = 1/8 (1/8 of
genes are identical as a result of consanguinity).
Consequences: If regular consanguin crosses are made
(for example brother/sister crosses in mice), at each
generation:
→ Fi tends towards a value of 1,
→ the individuals will become totally homozygotic.
Within each familly, all the individuals will be identical
in the genetic sense of the word.
Exactly the same genome.
Exactly the same genes.
This leads to the concept of the isogenetic line.
A1A1: p2 = 0.202 A1A2: 2 pq = 2 x 0.20 x 0.30
A2A2: q2 = 0.302 A1A3: 2 pr = 2 x 0.20 x 0.50
A3A3: r2 = 0.502 A2A3: 2 qr = 2 x 0.30 x 0.50
with p, q, r: the respective frequencies of the alleles
A1, A2 and A3.
b. Theoretical numbers
A1A1:
A2A2:
A3A3:
c.
0.202 x 400 =16
36
100
A1A2:
A1A3:
A2A3:
48
80
100
Comparison of the theoretical numbers and the
actual numbers found by a chi-squared test of
conformity
χ2 = (32 - 16)2/16 + .....+ (125 - 120)2/100 = 50
dd1 = 6 - 2 - 1 = 3; to a 5% threshold, [[chi]]2
calculated is greater than the value given in the
table (7.815) and is therefore highly significant.
Consequently the proportions of the genotypes do
not comply with those of the Hardy-Weinberg law,
the hypothesis of panmixia can be rejected.
3. Consanguinity has the effect of increasing the
frequency of homozygotes and of reducing that of
heterozygotes, relative to the proportions given by
the Hardy-Weinberg law. This is indeed what we
find. Consequently, consanguinity can account for
X- Multiallele system
The genotype frequencies at equilibrium for every AiAi
homozygote and every AiAj: heterozygote will be:
F(AiAi) = pi2(1 - F) + piF
F(AiAj) = 2pipj(1 - F)
X- 1 Exercice: Consanguinity for a locus
and three alleles
In a population of a diploid species with separate sexes
and separate generations, we are dealing with a triallele
autosomal locus (three possible allele states: A1, A2
and A3).
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
A1A3
60
Estimate the allele frequencies.
Can we assume that we have the proportions of
panmixia in the sample?
Knowing that there is no selection, no mutation, no
migration, no drift (large population), can
consanguinity account for the difference? What are
the theoretical proportions of the various
genotypes, knowing that the mean coefficient of
consanguinity is F?
Estimate the value of F from the proportions of the
sample.
3.
In other words, the increase is: (q2 + Fpq)/q2 = 1 + Fp/q
• when p = q: → = 1 + F ≅ 1
• when q is rare, p ≅ 1 → = 1 + F/q ≅ F/q, with Fmax
= 0.25 (incest), F is often of the order of 1 to 5 X 10-2
and q = 10-3 or 10-4, therefore a risk increased by a
factor of 10 to 103, which is generally the case for
recessive diseases. Isolates, with a high level of
consanguinity, allow unusual diseases to emerge.
A1A2
36
337
Consanguinity
Kalmes R, Huret JL
the significant differences between the previous
theroretical and actual numbers.
For the whole population, the theoretical genotype
frequencies are:
This article should be referenced as such:
Kalmes R, Huret JL. Consanguinity. Atlas
Cytogenet Oncol Haematol. 2002; 6(4):334-338.
A1A1: (1- F) p2 + Fp
A1A2: 2 pq (1 - F)
A2A2: (1 - F) q2 + Fq
A1A3: 2 pr (1 - F)
A3A3: (1 - F) r2 + Fr
A2A3: 2 qr (1 - F)
4. The frequency of A1A2 can be used simply to
calculate F:
frequency of A1A2 = 2 pq (1 - F)
36/400 = 2 x 0.20 x 0.30 (1 - F) therefore:
1 - F = 0.75
F = 0.25
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
338
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OPEN ACCESS JOURNAL AT INIST-CNRS
Educational Items Section
Genealogy and
Exercices
Coefficient
of Consanguinity,
Robert Kalmes
Institut de Recherche sur la Biologie de l'Insecte, IRBI - CNRS - ESA 6035, Av. Monge, F-37200 Tours,
France (RK)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Educ/ConsangGenealEng.html
DOI: 10.4267/2042/37915
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© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
This genealogy indicated by arrows is based on the fact
that every arrow starts at the ancestor and leads to the
offspring. In general, each individual is crossed by two
arrows. If only one parents is shared, then only one
arrow is shown in the genealogy.
GENEALOGY
Establishing the genealogy of an individual X, consists
of identifying the individuals who share part of their
genetic inheritance with X, because they are ancestors,
collaterals or descendants (collaterals: brothers, halfbrothers, cousins, uncles, nephews, etc ....).
Representation: there are several ways of representating
genealogies, in addition to the usual method used in
human genetics, and these may be more convenient
when one is studying Drosophila for example (see
below).
COEFFICIENT OF CONSANGUINITY
To calculate Fx, what we have to do is:
- Identify the parents of X (father and mother).
- Identify all the individuals in the genealogical tree
that are common ancestors of the father and mother of
X and who are the only individuals who can have
transmitted two identical alleles to X.
- An individual will be considered to be a common
ancestor if, starting from one of the two parents of X
are going back up the hereditary path from the
supposed common ancestor, it is then possible to come
back down again to the second parent of X without
breaking the sequential line of parenthood.
- In fact, each sequential line of parenthood describes
the Mendelian transmission of genes, and this means
that it can never pass more than once through the same
individual, nor change direction anywhere except in the
only common ancestor that it contains.
- Two lines of parenthood are different if the ordered
sequences of the individuals that compose them differ,
even if in only one place.
- Several different lines of parenthood can pass through
the same common ancestor.
Figure 1
A and B are the parents of E and F, who are in turn the
parents of H. C and D are the parents of G. C and
his/her offspring, G, are the parents of I, who, mated
with H, gives X.
Figure 2
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
339
Genealogy and Coefficient of Consanguinity, Exercices
Kalmes R
Individual B :
Descendant of a cross between half-siblings,
Only one line of parenthood.
Example 1: Brother - sister cross
Figure 6
Figure 3
Individual C:
Descendant of an uncle — niece cross,
2 lines of parenthood.
FC = 1/8
The parents of X (father and mother) are P and M.
A is a shared ancestor since P ---- A ---- M. P-A-M is a
line of parenthood with two links of parenthood. Here p
+ m = 2.
B is also a shared ancestor, since P ---- B ---- M. P-BM is a line of parenthood with two parenthood links.
Here p + m = 2.
Therefore, FX = _ (1/2 ) p+m+1 (1 + F Common ancestor)
gives here:
FX = ((1/2 ) 3 (1 + FA )) + ((1/2 ) 3 (1 + FB ))
Note: If, in a genealogy, it is not possible to find out
whether a common ancestor is also consanguine, by
convention it is assumed that (s)he is not. This is
applied to A and B, and so, FA = 0 and FB = 0
→ FX = (1/2 ) 3 + (1/2 ) 3 = 2 (1/2 ) 3 = 1/4
Some examples: Calculation of the coefficients of
consanguinity of individuals derived from various types
of crosses (the common ancestors are not related to
each other).
Figure 7
Individual D:
Descendant of a cross between first cousins
2 lines of parenthood
FD = 1/16
Figure 8
Individual E:
Descendant of a cross of cousins derived from first
cousins,
2 lines of parenthood.
FE = 1/64
Figure 4
Individual A:
Line of parenthood
Descendant of a brother—sister cross,
2 lines of parenthood.
FA = 1/4
Figure 9
This article should be referenced as such:
Kalmes R. Genealogy and Coefficient of Consanguinity,
Exercices. Atlas Genet Cytogenet Oncol Haematol. 2002;
6(4):339-340.
Figure 5
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
340
Atlas of Genetics and Cytogenetics
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OPEN ACCESS JOURNAL AT INIST-CNRS
Educational Items Section
Genetic Constitution of Consanguine Populations
Robert Kalmes, Jean-Loup Huret
Institut de Recherche sur la Biologie de l'Insecte, IRBI - CNRS - ESA 6035, Av. Monge, F-37200 Tours,
France (RK); Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers
Hospital, F-86021 Poitiers, France (JLH)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Educ/ConsangPopuEng.html
DOI: 10.4267/2042/37917
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Let us consider the case of a diallele gene, A1 and A2,
with a frequency of p and q in the parents.
Knowing that the children’s consanguinity is equal to
F, if a child is selected at random, what is the
probability that (s)he will be A1A1?
The two copies of gene A in this child may be:
The same by inheritance, an event with a probability of
F.
- or not be the same by inheritance, an event with a
probability of (1 - F)
In the first case, the probability that the first copy of
gene A will be A1, is equal to p, the frequency of A, in
the parents, and the probability that the second copy
will also be A1, is equal to 1, as both copies of the gene
are the same by inheritance. If the first one is A1, then
the second will also be A1.
In the second case, the probability that the first copy of
gene A will be A1 is equal to p, the frequency of A1 in
the parents, and the probability that the second copy
will also be A1 is still equal to p, because we are in a
situation in which the two copies of the gene are not
"the same by inheritance": if the first is A1, the second
is not automatically A1: it will only be A1 if it is
selected again, with a probability p.
Hence the frequency of the genotypes A1A1 in the
children:
frequency(A1A1) = Fp +(1-F)p2
The same logic, with A2 and q replacing A1 and p,
gives us the expected frequency of the A2A2 genotype
in the children:
frequency(A2A2) = Fq + (1-F)q2
What is the frequency that a randomly selected child
will be an A1A2 heterozygote?
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
The two copies of the gene A, present in this child may
be:
the same by inheritance, an event with a probability of
F;
or not be the same by inheritance, the opposite event,
with a probability of (1-F).
In the first case, the probability that the first copy of
gene A, A1, is equal to p, the frequency of A1 in the
parents, but the probability that the second copy will be
A2 is equal to 0, because we are in a situation in which
both copies of the gene are "the same by inheritance";
if the first is A1, then the second is A1 too.
In the second case, the probability that the first copy of
gene A is A1 is equal to p, the frequency of A1 in the
parents, and the probability that the second copy will be
A2 is equal to q, because here we are in a situation in
which both copies of the gene are not "the same by
inheritance": although it would also be possible for the
first to be A2 and the second A1, again with a
probability pq.
Hence the frequency of the A1A2 genotypes in the
children:
frequency(A1A2) = (1-F)2pq
These genotype frequencies are, after being developed
and factorized:
frequency(A1A1) = p2+ Fp(1-p) = p2+Fpq
frequency(A1A2) = 2 pq(1 - F)
frequency(A2A2) = q2 + Fq(1 - q) = q2 + Fpq
This article should be referenced as such:
Kalmes R, Huret JL. Genetic Constitution of Consanguine
Populations. Atlas Genet Cytogenet Oncol Haematol.
2002; 6(4):341.
341
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Educational Items Section
Prenatal Diagnosis
Louis Dallaire
Centre de Recherche, Hôpital Ste-Justine, Montréal, H3T 1C5, Canada (LD)
Published in Atlas Database: June 2002
Online updated version: http://AtlasGeneticsOncology.org/Educ/PrenatID30055ES.html
DOI: 10.4267/2042/37918
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© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Introduction
I- Families at risk
I- 1. Advanced maternal age
I- 2. Recurrence of numerical and structural chromosomal anomalies
I- 3. Fragile X syndrome and mental retardation
I- 4. Chromosomal instability
I- 5. Hereditary metabolic diseases
I- 6. Neural tube defects
II- Foetal Ultrasonography
II- 1. Ultrasonography
II- 2. Cardiac ultrasonography
II- 3. Markers suggesting the presence of a birth defect
II- 4. Foetal defects detected by ultrasound during the second trimester of pregnancy
II- 4.1. Nervous system anomalies
II- 4.2. Cardiovascular defects
II- 4.3. Thoracic anomalies
II- 4.4. Gastro intestinal malformations
II- 4.5. Urogenital malformations
II- 4.6. Musculo skeletal malformations
II- 4.7. Other anomalies
III- Techniques to obtain foetal tissues
III- 1. Amniocentesis
III- 2. Chorionic villus sampling (CVS)
III- 3. Cordocentesis
III- 4. Foetoscopy
III- 5. Fetal cells in maternal circulation
IV- Congenital anomalies due to single gene defects
V- Maternal serum markers
V- 1. Neural tube defects
V- 2. Trisomy 21 or Down syndrome
VI- Fluorescence in situ hybridization (FISH)
VII- Future perspectives
VII- 1. In utero treatment
VII- 2. Preimplantation diagnosis
VII- 3. Preconception screening
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
342
Prenatal Diagnosis
Dallaire L
couples at risk to envisage a pregnancy since an
alternative is now offered to them.
Introduction
Prenatal diagnosis answers the need to detect early in
pregnancy a number of foetal anomalies and genetic
diseases. The prenatal diagnosis of genetic diseases has
become widely available for pregnancies at risk in the
last three decades. In 1976 results of three multicentric
studies, realized in America and Europe, confirmed that
the tests performed on amniotic fluid cells (amniocytes)
were reliable and that the amniocentesis done during
the second trimester was a low risk procedure both for
the mother and her foetus.
Approximately 3% of viable foetuses would be born
with a severe anomaly. We now feel the impact of
prenatal diagnosis on the incidence of severe defects at
birth since a number of them will be diagnosed as early
as the end of the first trimester.
If a woman is known to be at risk to conceive a child
with a genetic disease a prenatal diagnosis could be
indicated. Knowing the nature of the anomaly to be
detected, this diagnosis can be realized in ultrasonography, with or without the study of amniotic fluid cells
or other foetal tissues. Before any intervention or use of
an invasive procedure is attempted, the sine qua non
rule of prenatal diagnosis is to make sure that the
genetic disease, likely to be present, is detectable and
that there is a possibility to show or exclude this defect
by testing the foetal tissues. Prenatal diagnosis allows
I- Families at risk
I- 1. Advanced maternal age
Women who are 35 or more at delivery have a higher
risk of giving birth to an infant with a chromosomal
defect due to a non disjunction. This increased risk is
due in part to ovum aging. This risk increases with age
(fig1) and frequently involves a trisomy 21 (Down
syndrome) that is the most frequent autosomal
anomaly. Trisomies 13 and 18 and sex chromosome
defects, XXY and XXX are frequently observed in
children born to mothers in this age group. Among
countries where prenatal diagnosis is available
selection criteria for the availability of prenatal
diagnosis is variable and amniocentesis will generally
be offered to pregnant women aged 35 or more at the
time of delivery. The availability of preventive medical
measures for pregnant women may include a screening
test for trisomy 21 by testing for maternal serum
markers ( see serological markers). This screening test,
to some extent, may allow the identification of women
more at risk of bearing a trisomic child and, if the test
was negative, reassure those who would elect not to
have an amniocentesis.
Figure 1 - Maternal age and incidence of trisomy 21 at birth.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
343
Prenatal Diagnosis
Dallaire L
Familial chromosomal translocation: one of the parents
is carrier of a balanced chromosomal translocation and
according to: 1- the type of translocation, 2-the
importance of the segments involved, 3- the
segregation of chromosomes in meiosis, there is
variable risk frequency:
- of spontaneous miscarriage due to a major
imbalance of the chromosomal complement
- to give birth to an affected infant with a viable
chromosomal defect
- that the foetus be a normal carrier like one of his
parents
- and the foetus may have a normal karyotype.
When an individual is found to have a structural
aberration the rule is to obtain the karyotype of his
parents and if necessary of the siblings: first to find the
origin of the defect and second to inform family
members of the reproduction risk if themselves are
normal physically but carriers of a translocation (fig 2).
I- 2. Recurrence of numerical and
structural chromosomal anomalies
All chromosomal defects (see also: Chromosomes
abnormalities ) resulting from a division error, or non
disjunction, can reoccur in more than 1% of cases in a
subsequent pregnancy and this risk can be very high for
a woman in the 30 years or less age group. At the age
of 20 the risk of trisomy 21 is approximately 1/2000,
1/1200 at 25, 1/900 at 30, 1/400 at 35, 1/100 at 40 and
1/40 at 45 years of age. This phenomenon also implies
that the aneuploidy can involve chromosomes other
than the one diagnosed initially. For instance a woman
who had conceived a child with a trisomy 21 could, in a
subsequent pregnancy, bear a child with a trisomy 13 or
18, or even a sex chromosome anomaly XXX or XXY.
It is also possible that a trisomy involving other
autosomes be non viable and result in an early
miscarriage.
Figure 2 - Partial family tree of a translocation 4;18.
(>60) at the Xq27.3 locus. If a child is affected, his
mother can be a carrier (we then speak of pre-mutation)
Of the syndrome and she is expected to have an
amplification of triplet CGG in the range of 60 to 200.
The amplification inhibits the expression of gene FMR1. Individuals of both sexes can be affected but males
are generally more severely affected.
If there is a positive family history of X linked mental
retardation a molecular study may allow the detection
We also suggest to karyotype couples who have a
personal or familial history of repeated foetal losses or
birth of children with mental retardation with or
without malformations or dysmorphism.
Individuals with a Fragile X syndrome (see also:
Dysgonosomies and related syndromes) have a peculiar
facies and mental retardation of variable severity. The
chromosomal study reveals a reduced density of the
chromatin in region Xq28. The genetic defect was
identified as an abnormal CGG triplet amplification
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
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Prenatal Diagnosis
Dallaire L
of a Fra X syndrome and if indicated a prenatal
diagnosis could be offered.
during the first 4 weeks of embryogenesis. The intake
of folic acid as soon as a pregnancy is planned, and for
the first two months has reduced the incidence and
recurrence of the neural tube defects.
It is highly recommended when there is a family
history of neural tube defect to monitor a pregnancy in
ultrasonography to make sure that both foetal cranium
and rachis are normal. In families at risk it is very
important to encourage the intake of folic acid as soon
as a woman plans a pregnancy or cease all means of
contraception.
Spina bifida aperta: opening of the tissues over the
bone defect with or without extrusion of the meninges;
it is occulta if the skin is normal.
Anencephaly: closure defect of the cranial vault.
The skull defect may be limited to a region of the
cranium and be variable in size; we then refer to an
encephalocele
Open lesions of the neural tube and cranium induce an
elevation of alpha-foetoproteins in amniotic fluid and
subsequently in maternal serum.
If there is a history of previous or familial
microcephaly a family study will help determining if
this is a hereditary defect: autosomal dominant or
recessive. Ultrasound examinations of the developing
foetus may facilitate the follow up of the head biparietal diameter and circumference, but only severe
growth deficiencies will likely be detected.
I- 4. Chromosomal instability
Some syndromes, called chromosome instability
syndromes manifest an unstable chromosomal
structure. We cite here as exemples Fanconi disease
characterized by anemia, growth delay, skeletal
anomalies and Bloom syndrome characterized by
anemia, dwarfism and light hypersensitivity. Both have
increased chromosomal breakages and affected
individuals are predisposed to cancer. These diseases
have an autosomal recessive mode of inheritance and
the recurrence risk is 25 % after the birth of an affected
child. Chromosomal exchanges are frequent in Fanconi
disease while sister chromatin exchanges are observed
in Bloom syndrome. Using appropriate techniques for
the culture of foetal cells and special staining
techniques for the chromosomes, these syndromes can
be diagnosed prenatally when the parents have been
shown to be heterozygous or normal carriers.
However the demonstration of specific mutations in
those rare diseases is not always feasible. If a prenatal
diagnosis is requested one can count on the molecular
study of foetal cells only if parental mutations have
been identified prior to the procedure.
I- 5. Hereditary metabolic diseases
a. Metabolic disease diagnosed in a child and finding of
an enzyme deficiency or a mutation that could be
detected in a subsequent pregnancy.
b. Known metabolic disease: the study of the parents
show that they are both carriers (heterozygous) and
that they have a 25% risk of conceiving an affected
child like in cystic fibrosis. Due to the high gene
frequency of this disease screening programs to
detect carriers are now being offered in some high
risk populations.
II- Foetal Ultrasonography
I- 6. Neural tube defects
Cardiac ultrasonography, that allows examination of
great vessels and heart chambers, is done usually
around the 20th week of pregnancy.
II- 1. Ultrasonography
Ultrasonography (Fig 3) makes use of ultrasounds to
study tissues and organs. It is applied from the first
trimester but it is only during the second trimester that
one can best evaluate foetal morphology and preferably
around the 18th week of gestation.
II- 2. Cardiac ultrasonography
Neural tube defects have a multifactorial etiology and
their incidence is widely variable. They used to be
more frequent in the British Isles, Canada, China and
other countries like Hungaria with an incidence of
5/1000 births and a recurrence risk of 5%. In France
and United States the incidence was more like 1/1000
with a low recurrence risk.
It has been shown, first in Great Britain, that the intake
of folic acid may help the closure of the neural tube and
lower the recurrence frequency in high risk
pregnancies. Closure of the neural tube takes place
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
II- 3. Markers suggesting the presence of a
birth defect
Ultrasonographic markers are variations observed
during the ultrasound session that will alert the
examiner to the possibility of an abnormal foetal
development or a genetic disease.
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Figure 3 - Fœtal ultrasound at 16 weeks of gestationThose markers can reveal for example the possibility of a chromosomal anomaly
such as a trisomy 21, 13, 18, or a chondrodysplasia.
II- 4. Foetal defects detected by ultrasound
during the second trimester of pregnancy
ULTRASOUND MARKERS SUGGESTING THE
PRESENCE OF A FOETAL ANOMALY
• Abdominal calcifications (meconial peritonitis)
• Bladder hypertrophy (urethral valve)
• Bone hypodensity (hypophosphatasia)
• Cerebral ventricles increased (hydrocephaly)
• Cono-truncal defect or defect of the heart common
trunk, manifested as a tetralogy of Fallot or a
vascular defect (Di George, and velo-cardio-facial
syndromes secondary to a deletion - del 22q11-)
• Cranial vault ossification defect (anencephaly)
• Cystic hygroma (Turner syndrome, 45X)
• Double buble in the gastric region (duodenal atresia)
• Endocardial cushion defect, or of the primary cardiac
septum, described as an atrium septal defect (trisomy
21)
• Facial hypoplasia and cleft lip ( trisomy 13 holoprosencephaly)
• Fractures (osteogenesis imperfecta)
• Increased number of choroidal cysts ( trisomy)
• Increased volume of cerebral ventricles
(hydrocephaly)
• Lemon sign, lemon shape head (spina bifida)
• Long bones shortening (bone dysplasia)
• Nucal skin folds increased (trisomy 21)
• Persistant flexed fingers (trisomy 18 arthrogryposis)
• Polydactyly (trisomy 13; Ellis Van-Creveld
syndrome)
• Pterygium colli (Turner syndrome; pterygium
multiple)
• Stomach unseen (oesophageal atresia)
• Thoracic deformity (skeletal dysplasia)
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
II- 4.1 Nervous system anomalies
• Anencephaly
• Cyst of the posterior fossa
• Encephalocele
• Facial dysplasia
• Holoprosencephaly (cerebral ventricle and facial
anomalies)
• Hydrocephaly
• Microcephaly
• Myelomeningocele
• Porencephaly ( cystic lesions of the brain)
• Rachischisis (significant vertebral closure defect)
• Spina-bifida
II- 4.2 Cardiovascular defects
• Arythmia
• Pericardial fluid collection
• Septal defect
• Situs inversus
• Valvular defect
• Vascular anomalies
• Ventricular hyperplasia
• Ventricular hypoplasia
II- 4.3 Thoracic anomalies
• Atresia of the oesophagus
• Diaphragmatic hernia
• Pleural effusion
• Intrathoracic cysts
II- 4.4 Gastro intestinal malformations
• Absence of abdominal muscles
• Ascites
• Cystic lymphangioma
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• Diaphragmatic hernia
• Intestinal atresia
• Laparoschisis (para-umbilical extrusion of abdominal
viscerae)
• Mesenteric cyst
• Omphalocele (umbilical hernia of abdominal
viscerae)
• Umbilical cord tumor (chorioangioma)
II- 4.5 Urogenital malformations
• Hydronephrosis
• Hydroureter
• Polycystic kidneys
• Renal agenesis
• Teratoma
• Urethral valve
II- 4.6 Musculo skeletal malformations
• Arthrogryposis
• Bone dysplasias
• Club foot
• Fractures
• Limb palsy
• Limb reduction defect
• Mineralization defect
• Pterygium colli
• Pterygium multiple
II- 4.7 Other anomalies
• Acardiac monster
• Amniotic band
• Cystic lesions
• Siamese twins
• Teratomas
• Tumors
diagnostic clinics perform amniocenteses between the
14th and 16th week of pregnancy. Studies have shown
an increased loss of amniotic fluid if the amniocentesis
done before the 12th week and there is a risk of skeletal
anomalies in particular of club feet secondary to
oligoamnios. According to the age of pregnancy from
10 to 30 ml of fluid are obtained during the procedure (
fig 5). Foetal cells from the upper digestive system,
urinary tract, skin and membranes are found in the fluid
and recuperated by centrifugation of the specimen.
They are then kept in culture for a period of 5 to10 days
in a culture medium to which calf serum has been
added. Cellular multiplication is then sufficient and
allows the preparation of microscopic slides allowing
the numerical and structural studies of the metaphasic
chromosomes. Treatment of chromosomes during the
slide preparation reveals segments of different intensity
or banding patterns. Those bands reflect a variable ratio
of AT;GC nucleotides on the chromatids and help to
identify chromosome pairs.
III- 2. Chorionic villus sampling (CVS)
The biopsy or aspiration of chorionic villi by the
vaginal route (fig 6) yields foetal cells, several of which
are in the process of dividing and can be analysed
during the hours following the procedure. There is a
risk of miscarriage and maternal cell contamination of
the specimen thus leading a number of clinicians to
abandon this procedure done before the 12th week of
pregnancy. Reduction limb defects have been reported
if the CVS is done towards the end of the first
trimester.
In special circumstances when the risk of genetic
disease is high as for instance in hereditary metabolic
diseases or if one of the parents is carrier of a balanced
chromosomal translocation, this technique has the
advantage of reaching a diagnosis around the 11th or
12th week of gestation.
III- Techniques to obtain foetal
tissues
III- 1. Amniocentesis
The amniocentesis (fig 4) is early if done around the
12th week of gestation. Today several prenatal
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
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Prenatal Diagnosis
Dallaire L
Figure 4 - Illustration of the amniocentesis procedure
.
Figure 5 - Illustration of the chorionic villus sampling procedure.III- 3. Cordocentesis
introducing a tube with optic fibres through the
abdomen and the uterus allowing to biopsy the foetus
or proceed to surgical interventions. For security
reasons this invasive technique is not a routine
procedure and is rarely utilized except in development
programs.
Blood can be obtained from the foetal cord under
ultrasound guidance. If at the end of second trimester
there is an urgent need to confirm a diagnosis or to
avoid extraordinary measures if there is there is a threat
of premature labor and the foetus is found to be
abnormal This procedure will allow a short term
chromosomal analysis from lymphocytes or an enzyme
study. The rapid cytogenetic study could also confirm
or exclude a chromosomal defect previously found in
the amniocytes. This approach can also be useful to
delineate mosaicism like for instance a trisomy 20
which usually has a favourable outcome or identify a
chromosomal marker confined to annexial tissues.
Cordocentesis has been used to study severe
immunological disorders by measuring adenosine
deaminase and doing T cells analysis.
III- 5. Fetal cells in maternal circulation
The presence of foetal cells in the maternal blood
stream could give us some information of the
chromosomal complement and the foetal genotype.
Research in this direction has been initiated several
years ago but up to date has yielded meagre results on
the efficacy of this non invasive procedure. Several
difficulties are encountered: the low frequency of
nucleated cells mean to isolate them, their identification
and genetic analysis. The venue of FISH technique and
other means to identify abnormal chromosomal
complements, and the PCR (polymerase chain reaction)
for molecular analysis have recently convince
III- 4. Foetoscopy
Foetoscopy is a technique that allows to visualize the
foetus around the end of the second trimester, by
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
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Prenatal Diagnosis
Dallaire L
researchers not to abandon this avenue which could be
a great asset to the prenatal diagnosis of genetic
disease.
VI- Fluorescence in situ
hybridization (FISH)
Fluorescense in situ hybridization makes use of
molecular probes marked in fluorescence that
correspond to a gene or DNA sequence and showing a
bright signal under UV microscope at a specific locus
on a chromosome. First the FISH technique can apply
to interphasic cells readily obtained at amniocentesis
and confirm the presence of an euploid or aneuploid
complement like for chromosomes X, Y, 13, 15, 18, 21.
This technique also applies to chromosomal markers
that can be detected in amniocytes with the help of
FISH. The technique can also be used to identify the
origin of supernumerary segments or confirm the loss
of specific sequences or a deletion on a given
chromosome.
IV- Congenital anomalies due to
single gene defects
Several congenital malformations have a hereditary
origin and their mode of transmission can be autosomal
dominant, recessive or X linked. Some syndromes
could be identified during the second trimester of
pregnancy if a major anomaly is detected at ultrasound
( like bone dysplasias). However if there is a history of
congenital anomaly of unknown etiology but seen in a
previous pregnancy, the mother could be reassured at
ultrasound if she is pregnant again. This measure
applies for instance in cases of omphalocele and
laparoschisis for which the risk of recurrence is low.
V- Maternal serum markers
Serological markers are normal proteins found in the
maternal circulation and if their level is abnormal it
will allow the detection of some foetal pathologies
early in pregnancy. The screening efficacy is increased
if both procedures foetal ultrasonography and marker
studies are completed simultaneously.
V- 1. Neural tube defects
Alpha-1 foetoprotein (AFP) constitute 20% of
circulating foetal proteins and its level varies with
foetal age at the time it is measured (fig 6). An increase
of AFP in the amniotic fluid will reflect on the maternal
serum level and may alert to the presence of an open
neural tube defect. A higher than normal level in the
amniotic fluid may be due to a skin lesion unseen at
ultrasound or may be due to foetal demise.
Figure 6 - Amniotic fluid AFP values during the second
trimester.
V- 2. Trisomy 21 or Down syndrome
VII- Future perspectives
AFP may also lead to suspecting a foetal trisomy 21 if
the maternal level is low according to the maternal age
around the 16th week of pregnancy.
A triple test is the combination of three maternal
serum markers: human chorionic gonagotrophin (hCG),
oestriol (uE3) and AFP. The measure of these proteins
at a given maternal and gestational ages, may give an
approximate risk figure that the foetus is trisomic (21).
The sensibility of this test is 60% and more based on
criteria used for the evaluation.
An early screening procedure based on the nucal
translucensy, hCG and a placental protein PAPP-A, is
available in some clinics from the end of the first
trimester to the 13th week of pregnancy. Nucal
translucency corresponds to the nucal tissue thickness.
A measure over 3 mm is considered suspicious at 12
weeks of pregnancy. This screening procedure has a
80% sensibility for trisomy 21 and can suggest the
presence of other pathologies. An abnormal result will
be validated by a chromosomal study.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
VII- 1. In utero treatment
The in utero treatment is limited to fluid aspiration for
instance in bladder hypertrophy secondary to an
urethral valve, and in some thoracic or abdominal fluid
collections. Other surgical procedures have been
completed like the insertion of a catheter in the bladder,
correction of certain heart defects, to name the most
common.
The finding of an abdominal wall defect (ex:
omphalocele) allows time for planning the mode of
delivery and alert neonate specialists and pediatric
surgeons to an immediate intervention at birth to
prevent systemic complications.
As part of indications for medical fœtal therapy, fœtal
arythmia can be corrected via a maternal medication
approach. Finally a restrictive phenyl-alanine diet,
prescribed as soon as a phenyl-cetonuric woman plans
a pregnancy, will prevent foetal complications and
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Prenatal Diagnosis
Dallaire L
especially a microcephaly and severe mental
retardation in the child.
The prenatal diagnosis of some metabolic diseases like
galactosemia or leucinosis will allow to plan ahead if
the foetus is sick and prescribe restrictive metabolic
milk for the infant to prevent early complications
secondary to abnormal metabolites.
For X linked diseases fœtal sexing is recommended
before proceeding to a molecular diagnosis.
VII- 3. Preconception screening
Preconception screening is a recent avenue in the field
of prevention. It implies the detection of gamete
anomalies and more specifically at the ovum level.
Recent publications refer to preconception diagnosis by
studying the first polar body in maturing ova: polar
bodies reflect the chromosomal complement and
genotype of the ovum that could be used in the in vitro
fertilization. In a recent literature report, a normal
ovum was selected from a mother known as a carrier of
a dominant gene for a severe form of Alzheimer
disease. It was reported that this ovum free of mutation
was used for the in vitro fertilization and a normal
infant was carried to term. The route is then traced for
diagnostic interventions based on gamete studies, but
ethic dilemmas will surge from any attempt to
manipulate germinal cells.
VII- 2. Preimplantation diagnosis
Preimplantation diagnosis is defined as the analysis of a
cell taken from a fertilized egg at, for instance, the
eight cell stage. It was introduced as an assisted
procreation technique in 1989 but it still considered a
research and development procedure. We do not know
yet if it is a secure and reliable procedure although to
date but according to literature reports a few dozens
infants born after this technique seem to have a normal
development. A limited number of laboratories in
Europe and America have the facilities and the
knowledge to offer this test as a diagnostic procedure.
To date this technique has been attempted in more than
one hundred pregnancies at risk and especially in
mucoviscidosis, Duchenne muscular dystrophy,
hemophilia A, alpha and beta thalassemia, bulbar
atrophy, Lesch Nyhan syndrome, incontinentia
pigmenti, Huntington disease, myotonic dystrophy.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
This article should be referenced as such:
Dallaire L. Prenatal Diagnosis. Atlas Genet Cytogenet
Oncol Haematol. 2002; 6(4):342-350.
350
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Prenatal Diagnosis
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4)
Dallaire L
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